chr10-54183497-A-G

Variant names:

• chr10-54183497-A-G
• rs876657951
• NM_033056.4:c.1537T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001384140.1(PCDH15):​c.1537T>C​(p.Ser513Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1537T>C	p.Ser513Pro	missense_variant	Exon 13 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1537T>C	p.Ser513Pro	missense_variant	Exon 13 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1537T>C	p.Ser513Pro	missense_variant	Exon 13 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1537T>C	p.Ser513Pro	missense_variant	Exon 13 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser513Pro variant in PCDH15 has not been previously reported in individual s with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Ser513Pro variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	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	0.052	D
MetaRNN	Uncertain	0.51	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	-0.67	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	.;.;.;.;.;.;.;N;N;.;N;N;.;N;.;.;N;N;N;N;D;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.29	.;.;.;.;.;.;.;T;T;.;T;T;.;T;.;.;T;T;T;T;T;T;T
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.77, 0.93	.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;P;D;D;.;D;P;D
Vest4		0.89
MutPred		0.32		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.83
MPC		0.061
ClinPred		0.73	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.68

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: rs876657951; hg19: chr10-55943257;