rs149510892

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000318024.9(USH1C):c.1285-7483C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,613,340 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

USH1C
ENST00000318024.9 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.08

Variant links:

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0054422915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.1906C>T	p.Arg636Cys	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 linkuse as main transcript	c.1285-7483C>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.1906C>T	p.Arg636Cys	missense_variant	18/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.1285-7483C>T		intron_variant		1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000331

AC:

AN:

251054

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000251

AC:

367

AN:

1461422

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.00335

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.00124

AC:

189

AN:

151918

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00396

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.00145

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH1C: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	This variant is associated with the following publications: (PMID: 12136232, 30245029) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2012

Arg636Cys in Exon 18 of USH1C: This variant has been reported in one individual with prelingual severe to profound deafness with no vision abnormalities (Ouyang 2002). However, this variant is not expected to have clinical significance beca use it has been identified in 0.5% (20/3738) of African American chromosomes fro m a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washin gton.edu/EVS; dbSNP rs149510892). In addition, this variant has been identified by our laboratory in a proband who carried two pathogenic variants in another ge ne. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.081

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.68

M_CAP

Benign

0.056

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.98

MutationTaster

Benign

0.68

D;D;D;D

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

REVEL

Benign

0.23

Sift

Benign

0.062

Sift4G

Benign

0.12

Vest4

0.30

MVP

0.37

MPC

0.082

ClinPred

0.019

GERP RS

4.0

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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