rs1283739647

Positions:

• chr10-54317344-C-A
• chr10-54317344-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000320301.11(PCDH15):​c.803G>T​(p.Cys268Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C268Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 ENST00000320301.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000320301.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.803G>T	p.Cys268Phe	missense_variant	8/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.803G>T	p.Cys268Phe	missense_variant	8/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.803G>T	p.Cys268Phe	missense_variant	8/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.803G>T	p.Cys268Phe	missense_variant	8/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	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	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	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	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.4	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.91
MutPred		0.40		Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);.;Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);.;Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);.;Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);.;.;.;Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);.;.;Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);Loss of catalytic residue at P267 (P = 0.0111);
MVP		0.91
MPC		0.26
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.77

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: rs1283739647; hg19: chr10-56077104;