10-54527824-C-T

Variant names:

• chr10-54527824-C-T
• rs1168400018
• NM_033056.4:c.145G>A

Variant summary

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

The NM_001384140.1(PCDH15):​c.145G>A​(p.Glu49Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,230 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80

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]

ENSG00000234173 (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 rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250090 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135132

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458230 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725440

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: 0.00000541

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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;T;.;.
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;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	0.034	D
MetaRNN	Uncertain	0.60	D;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	-0.80	T
MutationAssessor	Benign	0.90	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;.;.;.;.;.;N;D;.;N;.;N;N;.;N;.;.;N;N;.;N;N;N;D
REVEL	Benign	0.25
Sift	Benign	0.041	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;.;D;D;T;T
Sift4G	Uncertain	0.0060	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.0060, 0.0090, 0.034, 0.0010	.;.;.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;B;.;B;B;B;.
Vest4		0.87
MutPred		0.68		Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);.;Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);Gain of ubiquitination at E49 (P = 0.0138);
MVP		0.72
MPC		0.033
ClinPred		0.77	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.66

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: rs1168400018; hg19: chr10-56287584; COSMIC: COSV105201833;