chr10-53827426-G-T

Position:

• chr10-53827426-G-T

Variant summary

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

The NM_001384140.1(PCDH15):​c.4334C>A​(p.Ala1445Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

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]

PCDH15 (HGNC:):

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.4334C>A	p.Ala1445Glu	missense_variant	32/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4334C>A	p.Ala1445Glu	missense_variant	32/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4334C>A	p.Ala1445Glu	missense_variant	32/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4334C>A	p.Ala1445Glu	missense_variant	32/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248074 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134408

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460842 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726582

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.;.;.;.;T;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	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	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.31	.;.;.;.;.;.;.;.;N;.;N;.;.;N;.;.;N;N;N;.;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.011	.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D;D;.;D;D
Sift4G	Benign	0.15	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.48, 0.17, 0.82	.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;P;B;B;.;P;P
Vest4		0.51
MutPred		0.20		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);.;.;Gain of solvent accessibility (P = 0.0145);.;.;Gain of solvent accessibility (P = 0.0145);.;.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0145);.;.;.;.;Gain of solvent accessibility (P = 0.0145);
MVP		0.80
MPC		0.053
ClinPred		0.26	T
GERP RS		3.8
Varity_R		0.14
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146745502; hg19: chr10-55587186; COSMIC: COSV100220342;