rs140736502

chr10-54236859-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033056.4(PCDH15):c.949T>A(p.Ser317Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. S317S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.31

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011925429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.949T>A	p.Ser317Thr	missense_variant	9/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.949T>A	p.Ser317Thr	missense_variant	9/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.949T>A	p.Ser317Thr	missense_variant	9/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.949T>A	p.Ser317Thr	missense_variant	9/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251406 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135866

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461448 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727036

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152232 Hom.: 1 Cov.: 33 AF XY: 0.000793 AC XY: 59 AN XY: 74434

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.000262

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: 0.000473

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	The S317T variant in the PCDH15 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S317T variant is observed in 60/277126 (0.022%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). The S317T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret S317T as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 03, 2019	The p.Ser317Thr variant in PCDH15 has been previously reported by our laboratory in 1 individuals with hearing loss, and was also identified in 0.24% (60/24968) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This varia nt has also been reported in ClinVar (Variation iD 96235). Computational predict ion tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser317 Thr variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2016	- -

Autosomal recessive nonsyndromic hearing loss 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Oct 08, 2019

Two variants in this gene (PCDH15) were found to be in cis (both were inherited form the mother) in a young male with postlingual bilateral severe hearing loss -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N;.;.;.;.;.;N;N;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.056	T;.;.;.;.;.;D;D;.;D;.;D;T;.;T;.;.;T;T;T;.;T;T;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.39
MVP		0.76
MPC		0.030
ClinPred		0.072	T
GERP RS		1.6
Varity_R		0.26
gMVP		0.48

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: rs140736502; hg19: chr10-55996619;