chr10-54317413-C-A

Variant names:

• chr10-54317413-C-A
• rs562377533
• NM_033056.4:c.734G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033056.4(PCDH15):​c.734G>T​(p.Arg245Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R245Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30354416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.734G>T	p.Arg245Leu	missense_variant	Exon 8 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.734G>T	p.Arg245Leu	missense_variant	Exon 8 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.734G>T	p.Arg245Leu	missense_variant	Exon 8 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.734G>T	p.Arg245Leu	missense_variant	Exon 8 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251126 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461680 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 245 of the PCDH15 protein (p.Arg245Leu). This variant is present in population databases (rs562377533, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Benign	0.77
DEOGEN2	Benign	0.017	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	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;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.6	.;.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;N;N
PhyloP100		1.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.34	T;.;.;.;.;.;T;T;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Uncertain	0.058	T;.;T;T;T;T;T;T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.12, 0.34, 0.39, 1.0, 1.0, 0.20, 0.0020	.;.;.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;D;D;.;B;B;B
Vest4		0.38
MutPred		0.59		Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;.;.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);
MVP		0.74
MPC		0.14
ClinPred		0.62	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.52
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs562377533; hg19: chr10-56077173;