11-17498195-C-G

Position:

chr11-17498195-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153676.4(USH1C):c.2457G>C(p.Glu819Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,664 control chromosomes in the GnomAD database, including 225,739 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18621 hom., cov: 32)

Exomes 𝑓: 0.53 ( 207118 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.448

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8322468E-4).

BP6

Variant 11-17498195-C-G is Benign according to our data. Variant chr11-17498195-C-G is described in ClinVar as [Benign]. Clinvar id is 48003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17498195-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.2457G>C	p.Glu819Asp	missense_variant	24/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 linkuse as main transcript	c.1557G>C	p.Glu519Asp	missense_variant	19/21	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.2457G>C	p.Glu819Asp	missense_variant	24/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.1557G>C	p.Glu519Asp	missense_variant	19/21	1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74212

AN:

151930

Hom.:

18617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.547

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.442

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.499

GnomAD3 exomes

AF:

0.484

AC:

121669

AN:

251422

Hom.:

30411

AF XY:

0.490

AC XY:

66620

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.424

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.516

Gnomad EAS exome

AF:

0.308

Gnomad SAS exome

AF:

0.450

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.553

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.529

AC:

772714

AN:

1461614

Hom.:

207118

Cov.:

AF XY:

0.527

AC XY:

383308

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.418

Gnomad4 AMR exome

AF:

0.368

Gnomad4 ASJ exome

AF:

0.516

Gnomad4 EAS exome

AF:

0.305

Gnomad4 SAS exome

AF:

0.451

Gnomad4 FIN exome

AF:

0.529

Gnomad4 NFE exome

AF:

0.554

Gnomad4 OTH exome

AF:

0.507

GnomAD4 genome

AF:

0.488

AC:

74244

AN:

152050

Hom.:

18621

Cov.:

AF XY:

0.485

AC XY:

36041

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.425

Gnomad4 AMR

AF:

0.408

Gnomad4 ASJ

AF:

0.524

Gnomad4 EAS

AF:

0.299

Gnomad4 SAS

AF:

0.443

Gnomad4 FIN

AF:

0.537

Gnomad4 NFE

AF:

0.552

Gnomad4 OTH

AF:

0.496

Alfa

AF:

0.518

Hom.:

14963

Bravo

AF:

0.477

TwinsUK

AF:

0.548

AC:

2033

ALSPAC

AF:

0.559

AC:

2156

ESP6500AA

AF:

0.429

AC:

1886

ESP6500EA

AF:

0.559

AC:

4803

ExAC

AF:

0.487

AC:

59176

Asia WGS

AF:

0.372

AC:

1297

AN:

3478

EpiCase

AF:

0.556

EpiControl

AF:

0.562

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 1C

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 18A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.00018

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

N;.;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.068

Sift

Benign

0.089

T;T;D;D

Sift4G

Uncertain

0.037

D;D;D;D

Polyphen

0.013

B;.;B;.

Vest4

0.17

MutPred

0.35

Loss of ubiquitination at K524 (P = 0.1435);.;.;.;

MPC

0.072

ClinPred

0.012

GERP RS

3.4

Varity_R

0.24

gMVP

0.65

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