rs181306086

chr10-53807001-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001384140.1(PCDH15):c.4801G>A(p.Gly1601Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000243 in 1,613,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1601G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.77

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009886026).
• BP6: Variant 10-53807001-C-T is Benign according to our data. Variant chr10-53807001-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227836.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.4801G>A	p.Gly1601Ser	missense_variant	38/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.4801G>A	p.Gly1601Ser	missense_variant	38/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000326 AC: 81 AN: 248194 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134822

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461450 Hom.: 1 Cov.: 33 AF XY: 0.000127 AC XY: 92 AN XY: 727004

Gnomad4 AFR exome AF: 0.00460

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74296

Gnomad4 AFR AF: 0.00429

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.00166

ESP6500AA AF: 0.00542 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000365 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	p.Gly1543Ser in Exon 36C of PCDH15: This variant is not expected to have clinica l significance because it has been identified in 0.4% (37/9726) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs181306086). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2017	The G1543S variant in the PCDH15 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G1543S variant is observed in 37/9726 (0.38%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The G1543S variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G1543S as a variant of uncertain significance. -

PCDH15-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.;.;.;.;T;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	0.98	D;D
REVEL	Benign	0.25
Sift4G	Benign	0.25	T;.;T;T;T;T;D;D
Vest4		0.20
MVP		0.78
ClinPred		0.054	T
GERP RS		5.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs181306086; hg19: chr10-55566761; COSMIC: COSV100905036; COSMIC: COSV100905036;