rs565693539

chr10-54329622-G-Achr10-54329622-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033056.4(PCDH15):c.679C>T(p.Arg227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,601,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.679C>T	p.Arg227Cys	missense_variant	7/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.679C>T	p.Arg227Cys	missense_variant	7/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.679C>T	p.Arg227Cys	missense_variant	7/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.679C>T	p.Arg227Cys	missense_variant	7/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151796 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000679 AC: 17 AN: 250380 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1449988 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 722084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000726

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151914 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 12, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 227 of the PCDH15 protein (p.Arg227Cys). This variant is present in population databases (rs565693539, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 179459). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 09, 2018

The p.Arg227Cys variant in PCDH15 has been identified in the heterozygous state in two individuals with hearing loss, one of whom had clinical features of Usher syndrome but was found to have an alternate genetic etiology (LMM data). This v ariant has also been identified in 0.04% (14/34350) of Latino chromosomes by gno mAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variati on ID 179459). Computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. In summary, the c linical significance of the p.Arg227Cys variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. -

Usher syndrome type 1F Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;.;T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	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	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.8	D;.;.;.;.;.;D;D;.;D;.;D;D;.;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.;.;.;.;.;D;D;.;D;.;D;D;.;.;.;D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0010	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, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;D;D;.;D;D;D
Vest4		0.69
MutPred		0.63		Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);
MVP		0.79
MPC		0.24
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.66

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: rs565693539; hg19: chr10-56089382; COSMIC: COSV57340909;