chr10-53827546-C-T

Position:

chr10-53827546-C-T

Variant summary

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

The NM_001384140.1(PCDH15):c.4214G>A(p.Arg1405His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000384 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 6.92

Variant links:

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 links:

PCDH15 (HGNC:):

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.4214G>A	p.Arg1405His	missense_variant, splice_region_variant	32/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.4214G>A	p.Arg1405His	missense_variant, splice_region_variant	32/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.4214G>A	p.Arg1405His	missense_variant, splice_region_variant	32/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4214G>A	p.Arg1405His	missense_variant, splice_region_variant	32/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249056

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134826

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1F

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 06, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg1405His variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 26969326) and has been identified in 0.008% (2/24962) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs143538460). This variant has also been reported in ClinVar (Variation ID#: 550153) and has been interpreted as a variant of uncertain significance by Counsyl, Invitae, and Natera, Inc.. Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1405His variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1405 of the PCDH15 protein (p.Arg1405His). This variant is present in population databases (rs143538460, gnomAD 0.008%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 26969326). This variant is also known as NM_001142763:c.4229G>A (p.Arg1410His). ClinVar contains an entry for this variant (Variation ID: 550153). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	Observed with the PCDH15 N221S variant in a patient with hearing loss in published literature; it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sloan-Heggen et al., 2016; described as R1410H using alternate nomenclature); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26969326) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 07, 2024

Variant summary: PCDH15 c.4214G>A (p.Arg1405His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249056 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4214G>A has been reported in the literature as NM_001142763.2:c.4229G>A (p.Arg1410His), in a non-informative genotype in at-least one individual with a clinical diagnosis of autosomal recessive non-syndromic hearing loss (second allele classification and/or phase not clearly specified) (example, Sloan-Heggen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 550153). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

T;.;.;.;.;T;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

0.11

MetaRNN

Uncertain

0.66

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.8

.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.6

.;.;.;.;.;.;.;.;N;.;N;.;.;N;.;.;N;N;N;.;N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0020

.;.;.;.;.;.;.;.;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

Polyphen

1.0

.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;.;D;D

Vest4

0.88

MVP

0.84

MPC

0.24

ClinPred

0.63

GERP RS

5.4

Varity_R

0.20

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over