rs61730754

Positions:

• chr10-54153182-C-A
• chr10-54153182-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000320301.11(PCDH15):​c.1702G>T​(p.Ala568Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A568T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 ENST00000320301.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3539403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1702G>T	p.Ala568Ser	missense_variant	14/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1702G>T	p.Ala568Ser	missense_variant	14/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1702G>T	p.Ala568Ser	missense_variant	14/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.1702G>T	p.Ala568Ser	missense_variant	14/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.018	T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	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	0.036	D
MetaRNN	Benign	0.35	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	-0.77	T
MutationAssessor	Benign	1.0	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	.;.;.;.;.;.;.;N;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.13	.;.;.;.;.;.;.;T;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Benign	0.088	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.76, 0.99, 0.99, 0.97, 0.97, 0.27	.;.;.;.;.;.;.;.;.;.;.;P;.;D;.;.;D;D;D;.;D;D;B
Vest4		0.42
MutPred		0.46		Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);.;Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);.;Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);.;.;.;Gain of glycosylation at A568 (P = 0.0924);.;.;.;Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);.;.;Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);Gain of glycosylation at A568 (P = 0.0924);
MVP		0.72
MPC		0.087
ClinPred		0.70	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61730754; hg19: chr10-55912942; COSMIC: COSV57377023;