NM_018901.4:c.81C>A

Variant names:

• chr5-140856129-C-A
• rs149039484
• NM_018901.4:c.81C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018901.4(PCDHA10):​c.81C>A​(p.Ser27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,598,096 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0016 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (281 hom.)
• Consequence: PCDHA10 NM_018901.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.815

Genes affected

PCDHA10 (HGNC:8664): (protocadherin alpha 10) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA3 (HGNC:8669): (protocadherin alpha 3) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA6 (HGNC:8672): (protocadherin alpha 6) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA8 (HGNC:8674): (protocadherin alpha 8) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA9 (HGNC:8675): (protocadherin alpha 9) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA4 (HGNC:8670): (protocadherin alpha 4) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA7 (HGNC:8673): (protocadherin alpha 7) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA5 (HGNC:8671): (protocadherin alpha 5) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA@ (HGNC:8662):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010838956).
• BS2: High Homozygotes in GnomAd4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA10	NM_018901.4	c.81C>A	p.Ser27Arg	missense_variant	Exon 1 of 4	ENST00000307360.6	NP_061724.1
PCDHA1	NM_018900.4	c.2394+67445C>A		intron_variant	Intron 1 of 3	ENST00000504120.4	NP_061723.1
PCDHA3	NM_018906.3	c.2394+52538C>A		intron_variant	Intron 1 of 3	ENST00000522353.3	NP_061729.1
PCDHA6	NM_018909.4	c.2394+25644C>A		intron_variant	Intron 1 of 3	ENST00000529310.6	NP_061732.1
PCDHA8	NM_018911.3	c.2394+12414C>A		intron_variant	Intron 1 of 3	ENST00000531613.2	NP_061734.1
PCDHA9	NM_031857.2	c.2394+5240C>A		intron_variant	Intron 1 of 3	ENST00000532602.2	NP_114063.1
PCDHA2	NM_018905.3	c.2388+58777C>A		intron_variant	Intron 1 of 3	ENST00000526136.2	NP_061728.1
PCDHA4	NM_018907.4	c.2385+46557C>A		intron_variant	Intron 1 of 3	ENST00000530339.2	NP_061730.1
PCDHA7	NM_018910.3	c.2355+19391C>A		intron_variant	Intron 1 of 3	ENST00000525929.2	NP_061733.1
PCDHA5	NM_018908.3	c.2352+32002C>A		intron_variant	Intron 1 of 3	ENST00000529859.2	NP_061731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA10	ENST00000307360.6	c.81C>A	p.Ser27Arg	missense_variant	Exon 1 of 4	1	NM_018901.4	ENSP00000304234.5
PCDHA1	ENST00000504120.4	c.2394+67445C>A		intron_variant	Intron 1 of 3	1	NM_018900.4	ENSP00000420840.3
PCDHA3	ENST00000522353.3	c.2394+52538C>A		intron_variant	Intron 1 of 3	1	NM_018906.3	ENSP00000429808.2
PCDHA6	ENST00000529310.6	c.2394+25644C>A		intron_variant	Intron 1 of 3	1	NM_018909.4	ENSP00000433378.1
PCDHA8	ENST00000531613.2	c.2394+12414C>A		intron_variant	Intron 1 of 3	1	NM_018911.3	ENSP00000434655.1
PCDHA9	ENST00000532602.2	c.2394+5240C>A		intron_variant	Intron 1 of 3	1	NM_031857.2	ENSP00000436042.2
PCDHA2	ENST00000526136.2	c.2388+58777C>A		intron_variant	Intron 1 of 3	1	NM_018905.3	ENSP00000431748.1
PCDHA4	ENST00000530339.2	c.2385+46557C>A		intron_variant	Intron 1 of 3	1	NM_018907.4	ENSP00000435300.1
PCDHA7	ENST00000525929.2	c.2355+19391C>A		intron_variant	Intron 1 of 3	1	NM_018910.3	ENSP00000436426.1
PCDHA5	ENST00000529859.2	c.2352+32002C>A		intron_variant	Intron 1 of 3	1	NM_018908.3	ENSP00000436557.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 238 AN: 150020 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000400

Gnomad ASJ AF: 0.00321

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000863

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00280

Gnomad OTH AF: 0.00243

GnomAD3 exomes AF: 0.00128 AC: 319 AN: 248850 Hom.: 27 AF XY: 0.00136 AC XY: 183 AN XY: 134592

Gnomad AFR exome AF: 0.000746

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00233

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000881

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00212 AC: 3074 AN: 1447960 Hom.: 281 Cov.: 31 AF XY: 0.00211 AC XY: 1522 AN XY: 720456

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000982

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00159 AC: 238 AN: 150136 Hom.: 16 Cov.: 32 AF XY: 0.00149 AC XY: 109 AN XY: 73322

Gnomad4 AFR AF: 0.000463

Gnomad4 AMR AF: 0.000400

Gnomad4 ASJ AF: 0.00321

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000863

Gnomad4 NFE AF: 0.00280

Gnomad4 OTH AF: 0.00241

Alfa AF: 0.00128 Hom.: 6

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00316 AC: 27

ExAC AF: 0.00123 AC: 148

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	.;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	M;M;M
PROVEAN	Uncertain	-4.0	.;D;D
REVEL	Benign	0.20
Sift	Benign	0.054	.;T;T
Sift4G	Uncertain	0.024	D;T;T
Polyphen		0.18	B;B;B
Vest4		0.12
MutPred		0.36		Gain of methylation at S27 (P = 0.0477);Gain of methylation at S27 (P = 0.0477);Gain of methylation at S27 (P = 0.0477);
MVP		0.73
ClinPred		0.022	T
GERP RS		2.5
Varity_R		0.27
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149039484; hg19: chr5-140235714;