10-53857257-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_033056.4(PCDH15):c.3724G>A(p.Val1242Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,610,120 control chromosomes in the GnomAD database, including 2 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. V1242V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 7.71

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018776953).
• BP6: Variant 10-53857257-C-T is Benign according to our data. Variant chr10-53857257-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178521.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.3724G>A	p.Val1242Met	missense_variant	28/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.3724G>A	p.Val1242Met	missense_variant	28/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3724G>A	p.Val1242Met	missense_variant	28/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.3724G>A	p.Val1242Met	missense_variant	28/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151800 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000375 AC: 94 AN: 250950 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135692

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00457

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000132 AC: 192 AN: 1458202 Hom.: 1 Cov.: 29 AF XY: 0.000113 AC XY: 82 AN XY: 725650

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000250 AC: 38 AN: 151918 Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74260

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000526

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00426

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 01, 2016	p.Val1242Met in exon 28 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.5% (47/8638) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs201137087). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2022	Variant summary: PCDH15 c.3724G>A (p.Val1242Met) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 250950 control chromosomes, predominantly at a frequency of 0.0046 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3724G>A has been reported in the literature in individuals affected with Usher Syndrome Type 1, hereditary hearing loss and inherited retinal dystrophies (Yoshimura_2014, Chen_2016, Liu_2020). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three labs classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1F Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 26, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
REVEL	Pathogenic	0.82
Sift4G	Uncertain	0.0030	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4		0.94
MVP		0.84
MPC		0.22
ClinPred		0.072	T
GERP RS		5.2
Varity_R		0.26
gMVP		0.69

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: rs201137087; hg19: chr10-55617017;