11-17498195-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E819delinsDAD) has been classified as Uncertain significance.

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

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 48003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.2457G>C	p.Glu819Asp	missense_variant	Exon 24 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 link	c.1557G>C	p.Glu519Asp	missense_variant	Exon 19 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.2457G>C	p.Glu819Asp	missense_variant	Exon 24 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9 link	c.1557G>C	p.Glu519Asp	missense_variant	Exon 19 of 21	1	NM_005709.4	ENSP00000317018.4

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

GnomAD2 exomes

AF:

0.484

AC:

121669

AN:

251422

AF XY:

0.490

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 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

African (AFR)

AF:

0.418

AC:

13992

AN:

33476

American (AMR)

AF:

0.368

AC:

16435

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.516

AC:

13497

AN:

26132

East Asian (EAS)

AF:

0.305

AC:

12115

AN:

39692

South Asian (SAS)

AF:

0.451

AC:

38939

AN:

86244

European-Finnish (FIN)

AF:

0.529

AC:

28259

AN:

53408

Middle Eastern (MID)

AF:

0.462

AC:

2664

AN:

5766

European-Non Finnish (NFE)

AF:

0.554

AC:

616212

AN:

1111792

Other (OTH)

AF:

0.507

AC:

30601

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

20054

40108

60163

80217

100271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17180

34360

51540

68720

85900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.488

AC:

74244

AN:

152050

Hom.:

18621

Cov.:

AF XY:

0.485

AC XY:

36041

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.425

AC:

17596

AN:

41442

American (AMR)

AF:

0.408

AC:

6243

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

1820

AN:

3470

East Asian (EAS)

AF:

0.299

AC:

1542

AN:

5160

South Asian (SAS)

AF:

0.443

AC:

2136

AN:

4820

European-Finnish (FIN)

AF:

0.537

AC:

5679

AN:

10566

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.552

AC:

37540

AN:

67982

Other (OTH)

AF:

0.496

AC:

1049

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1916

3832

5748

7664

9580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 1C

Benign:4

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18A

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

0.45

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

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over