rs397517453

Positions:

• chr10-54022979-A-T

Variant summary

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

The NM_033056.4(PCDH15):​c.2439T>A​(p.Asp813Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.43

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=0.36280835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2439T>A	p.Asp813Glu	missense_variant	19/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2439T>A	p.Asp813Glu	missense_variant	19/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2439T>A	p.Asp813Glu	missense_variant	19/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.2439T>A	p.Asp813Glu	missense_variant	19/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251336 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2012

The Asp813Glu variant in PCDH15 has not been reported in the literature nor prev iously identified by our laboratory. In addition, this variant has not been iden tified in large and broad European American or African American populations by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computati onal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyP hen2, and SIFT) do not provide strong support for or against an impact to the pr otein. In summary, additional information is needed to fully assess the clinical significance of the Asp813Glu variant. -

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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
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
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	.;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.38	.;.;.;.;.;.;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Uncertain	0.0030	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 1.0, 1.0, 0.99	.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.77
MutPred		0.67		Loss of ubiquitination at K808 (P = 0.0795);Loss of ubiquitination at K808 (P = 0.0795);.;Loss of ubiquitination at K808 (P = 0.0795);Loss of ubiquitination at K808 (P = 0.0795);.;Loss of ubiquitination at K808 (P = 0.0795);.;.;.;Loss of ubiquitination at K808 (P = 0.0795);.;.;.;.;Loss of ubiquitination at K808 (P = 0.0795);Loss of ubiquitination at K808 (P = 0.0795);.;.;.;Loss of ubiquitination at K808 (P = 0.0795);Loss of ubiquitination at K808 (P = 0.0795);
MVP		0.66
MPC		0.19
ClinPred		0.49	T
GERP RS		2.0
Varity_R		0.075
gMVP		0.51

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: rs397517453; hg19: chr10-55782739;