chr10-53807001-C-T

Variant names:

• chr10-53807001-C-T
• rs181306086
• NM_001384140.1:c.4801G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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
• Publications: 2 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.4801G>A	p.Gly1601Ser	missense_variant	Exon 38 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2	c.4801G>A	p.Gly1601Ser	missense_variant	Exon 38 of 38		NM_001384140.1	ENSP00000495195.1

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

GnomAD2 exomes AF: 0.000326 AC: 81 AN: 248194 AF XY: 0.000230

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 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

African (AFR) AF: 0.00460 AC: 154 AN: 33470

American (AMR) AF: 0.000291 AC: 13 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111704

Other (OTH) AF: 0.000282 AC: 17 AN: 60366

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

African (AFR) AF: 0.00429 AC: 178 AN: 41468

American (AMR) AF: 0.000722 AC: 11 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000731 Hom.: 1

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

May 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Aug 31, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 26, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCDH15-related disorder Benign:1

Dec 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		4.8
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
Mutation Taster		=40/60	disease causing

Splicing

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

Other links and lift over

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