chr10-54020215-C-T

Position:

• chr10-54020215-C-T

Variant summary

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

The NM_001384140.1(PCDH15):​c.2728G>A​(p.Ala910Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16

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/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2728G>A	p.Ala910Thr	missense_variant	20/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2728G>A	p.Ala910Thr	missense_variant	20/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2728G>A	p.Ala910Thr	missense_variant	20/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2728G>A	p.Ala910Thr	missense_variant	20/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461482 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH15 protein function. ClinVar contains an entry for this variant (Variation ID: 1524293). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 910 of the PCDH15 protein (p.Ala910Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.012	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	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	0.021	T
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.82	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.90	.;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.34	.;.;.;.;.;.;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Uncertain	0.041	D;.;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;T
Polyphen		0.86, 1.0, 0.99, 1.0, 1.0, 0.97, 0.68	.;.;.;.;.;.;.;.;.;.;P;.;D;.;.;D;D;D;.;D;D;P
Vest4		0.91
MutPred		0.71		Gain of glycosylation at A910 (P = 0.034);Gain of glycosylation at A910 (P = 0.034);.;Gain of glycosylation at A910 (P = 0.034);Gain of glycosylation at A910 (P = 0.034);.;Gain of glycosylation at A910 (P = 0.034);.;.;.;Gain of glycosylation at A910 (P = 0.034);.;.;.;.;Gain of glycosylation at A910 (P = 0.034);Gain of glycosylation at A910 (P = 0.034);.;.;.;Gain of glycosylation at A910 (P = 0.034);Gain of glycosylation at A910 (P = 0.034);
MVP		0.66
MPC		0.17
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.25
gMVP		0.70

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: rs139175351; hg19: chr10-55779975;