rs754391973

chr10-53961790-G-Achr10-53961790-G-Cchr10-53961790-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_033056.4(PCDH15):c.2971C>T(p.Arg991Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,610,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-53961790-G-A is Pathogenic according to our data. Variant chr10-53961790-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 224747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53961790-G-A is described in Lovd as [Pathogenic]. Variant chr10-53961790-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.2971C>T	p.Arg991Ter	stop_gained	22/33	ENST00000320301.11
PCDH15	NM_001384140.1 linkuse as main transcript	c.2971C>T	p.Arg991Ter	stop_gained	22/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.2971C>T	p.Arg991Ter	stop_gained	22/33	1	NM_033056.4		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.2971C>T	p.Arg991Ter	stop_gained	22/38		NM_001384140.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250854

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135594

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1458658

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725606

show subpopulations

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:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1F

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg991Ter variant in PCDH15 has been reported in at least 2 individuals with Usher syndrome type 1F (PMID: 16679490, 32531858), and has been identified in 0.004% (4/113468) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs754391973). 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. This variant has also been reported in ClinVar (Variation ID#: 224747) and has been interpreted as pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Invitae, and Centre for Genomic Medicine (Central Manchester University Hospitals). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg991Ter variant is pathogenic (PMID: 32531858). This nonsense variant leads to a premature termination codon at position 991, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2018	Variant summary: PCDH15 c.2971C>T (p.Arg991X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 246060 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (2e-05 vs 0.0032), allowing no conclusion about variant significance. The c.2971C>T variant has been reported in the literature in multiple homozygous individuals affected with Usher Syndrome Type 1F. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal recessive nonsyndromic hearing loss 23

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 26, 2023

- -

Usher syndrome type 1D

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Aug 28, 2015

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 29, 2023

This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16679490, 24618850, 29568747). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg991*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs754391973, gnomAD 0.004%). This variant is also known as c.2758C>T (p.R920*). ClinVar contains an entry for this variant (Variation ID: 224747). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.76

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;D;D;D;D

Vest4

0.92

GERP RS

3.1

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