NM_033056.4:c.1583T>C

Variant names:

• chr10-54183451-A-G
• NM_033056.4:c.1583T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033056.4(PCDH15):​c.1583T>C​(p.Val528Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000048 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1583T>C	p.Val528Ala	missense_variant	Exon 13 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1583T>C	p.Val528Ala	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.1583T>C	p.Val528Ala	missense_variant	Exon 13 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1583T>C	p.Val528Ala	missense_variant	Exon 13 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459424 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726230

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: 0.00000631

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	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	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	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.6	.;.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	.;.;.;.;.;.;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	.;.;.;.;.;.;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;.;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, 0.99, 1.0, 0.98	.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.89
MutPred		0.81		Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);.;Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);.;Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);.;.;.;Loss of stability (P = 0.0445);.;.;.;Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);.;.;Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);Loss of stability (P = 0.0445);
MVP		0.83
MPC		0.23
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.76
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-55943211;