5-140841325-G-A

Variant summary

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

The NM_018911.3(PCDHA8):c.4G>A(p.Asp2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,608,142 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (125 hom.)
• Consequence: PCDHA8 NM_018911.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00561288).
• BP6: Variant 5-140841325-G-A is Benign according to our data. Variant chr5-140841325-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2655766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA8	NM_018911.3	c.4G>A	p.Asp2Asn	missense_variant	1/4	ENST00000531613.2
PCDHA1	NM_018900.4	c.2394+52641G>A		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+43973G>A		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+37734G>A		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+31753G>A		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+17198G>A		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+10840G>A		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+4587G>A		intron_variant		ENST00000525929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA8	ENST00000531613.2	c.4G>A	p.Asp2Asn	missense_variant	1/4	1	NM_018911.3	P1
PCDHA1	ENST00000504120.4	c.2394+52641G>A		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+37734G>A		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+4587G>A		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+43973G>A		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+10840G>A		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+17198G>A		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+31753G>A		intron_variant		1	NM_018907.4	P1

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152042 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00690

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00800

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00460 AC: 1140 AN: 247770 Hom.: 17 AF XY: 0.00430 AC XY: 576 AN XY: 133974

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00297

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00834

Gnomad NFE exome AF: 0.00698

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00596 AC: 8683 AN: 1455982 Hom.: 125 Cov.: 33 AF XY: 0.00587 AC XY: 4250 AN XY: 723896

Gnomad4 AFR exome AF: 0.000693

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00901

Gnomad4 NFE exome AF: 0.00689

Gnomad4 OTH exome AF: 0.00564

GnomAD4 genome AF: 0.00475 AC: 722 AN: 152160 Hom.: 10 Cov.: 33 AF XY: 0.00453 AC XY: 337 AN XY: 74398

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00690

Gnomad4 NFE AF: 0.00800

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00475 Hom.: 0

Bravo AF: 0.00378

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00475 AC: 577

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00487

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

Feb 01, 2023

PCDHA8: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Benign	0.85
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.057
Sift	Benign	0.43	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.013	B;B
Vest4		0.061
MVP		0.43
ClinPred		0.0026	T
GERP RS		1.5
Varity_R		0.054
gMVP		0.29

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: rs111298048; hg19: chr5-140220910; COSMIC: COSV65340246; COSMIC: COSV65340246;