5-140856227-A-C

Position:

• chr5-140856227-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018901.4(PCDHA10):​c.179A>C​(p.Gln60Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,597,986 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (320 hom.)
• Consequence: PCDHA10 NM_018901.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.449

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]

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]

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]

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]

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]

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]

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071617067).
• BP6: Variant 5-140856227-A-C is Benign according to our data. Variant chr5-140856227-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2655777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA10	NM_018901.4	c.179A>C	p.Gln60Pro	missense_variant	1/4	ENST00000307360.6
PCDHA1	NM_018900.4	c.2394+67543A>C		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+58875A>C		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+52636A>C		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+46655A>C		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+32100A>C		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+25742A>C		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+19489A>C		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+12512A>C		intron_variant		ENST00000531613.2
PCDHA9	NM_031857.2	c.2394+5338A>C		intron_variant		ENST00000532602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA10	ENST00000307360.6	c.179A>C	p.Gln60Pro	missense_variant	1/4	1	NM_018901.4	P1
PCDHA1	ENST00000504120.4	c.2394+67543A>C		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+52636A>C		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+19489A>C		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+58875A>C		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+25742A>C		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+32100A>C		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+46655A>C		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+12512A>C		intron_variant		1	NM_018911.3	P1
PCDHA9	ENST00000532602.2	c.2394+5338A>C		intron_variant		1	NM_031857.2	P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 506 AN: 150040 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.000904

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000934

Gnomad ASJ AF: 0.000878

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.00407 AC: 1010 AN: 248376 Hom.: 75 AF XY: 0.00436 AC XY: 586 AN XY: 134534

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000608

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00755

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00283 AC: 4099 AN: 1447830 Hom.: 320 Cov.: 32 AF XY: 0.00299 AC XY: 2155 AN XY: 720424

Gnomad4 AFR exome AF: 0.000870

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.000467

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00722

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00276

GnomAD4 genome AF: 0.00337 AC: 506 AN: 150156 Hom.: 35 Cov.: 32 AF XY: 0.00461 AC XY: 338 AN XY: 73368

Gnomad4 AFR AF: 0.000901

Gnomad4 AMR AF: 0.000933

Gnomad4 ASJ AF: 0.000878

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.00252

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.00241 Hom.: 8

Bravo AF: 0.00180

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00152 AC: 13

ExAC AF: 0.00382 AC: 462

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PCDHA10: BP4, BS2; PCDHA2: BS2; PCDHA3: BS2; PCDHA4: BS2; PCDHA5: BS2; PCDHA6: BS2; PCDHA7: BS2; PCDHA8: BS2; PCDHA9: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.82
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.28	T;T;T
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N;N;N
MutationTaster	Benign	0.99	D;D;N;N;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.13
MVP		0.18
ClinPred		0.0036	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.67

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: rs149352769; hg19: chr5-140235812; COSMIC: COSV100247960; COSMIC: COSV100247960;