rs1554833865

Positions:

• chr10-54195886-C-T

Variant summary

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

The ENST00000320301.11(PCDH15):​c.1102G>A​(p.Glu368Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E368G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 ENST00000320301.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.87

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.1102G>A	p.Glu368Lys	missense_variant	11/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1102G>A	p.Glu368Lys	missense_variant	11/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1102G>A	p.Glu368Lys	missense_variant	11/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.1102G>A	p.Glu368Lys	missense_variant	11/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2017

The p.Glu368Lys variant in PCDH15 has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analyses do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Glu368Lys var iant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.1102G>A (p.E368K) alteration is located in exon 11 (coding exon 10) of the PCDH15 gene. This alteration results from a G to A substitution at nucleotide position 1102, causing the glutamic acid (E) at amino acid position 368 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.051	T;.;.;.;.;T;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	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
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.67	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	-0.83	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D;.;.;.;.;.;N;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;.;.;.;.;.;T;.;T;.;D;D;.;D;.;.;D;D;D;.;T;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
Polyphen		1.0, 1.0, 0.99, 1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.86
MutPred		0.42		Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);.;Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);.;Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);.;Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);.;.;.;Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);.;.;Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);Gain of ubiquitination at E368 (P = 0.0203);
MVP		0.71
MPC		0.22
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.69

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: rs1554833865; hg19: chr10-55955646;