rs41282936

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153676.4(USH1C):c.819+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,136 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.014 ( 164 hom. )

Consequence

USH1C
NM_153676.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.326

Publications

6 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 (BayesDel_noAF=-0.78).

BP6

Variant 11-17523409-C-G is Benign according to our data. Variant chr11-17523409-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 48025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1608/152300) while in subpopulation NFE AF = 0.0175 (1189/68024). AF 95% confidence interval is 0.0167. There are 17 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.819+10G>C		intron_variant	Intron 10 of 26	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.819+10G>C		intron_variant	Intron 10 of 20	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.819+10G>C		intron_variant	Intron 10 of 26	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.819+10G>C		intron_variant	Intron 10 of 20	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1608

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00914

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0107

AC:

2689

AN:

251442

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.0212

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0172

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.0136

AC:

19859

AN:

1461836

Hom.:

164

Cov.:

AF XY:

0.0133

AC XY:

9705

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33480

American (AMR)

AF:

0.00523

AC:

234

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

540

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000730

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0118

AC:

630

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0158

AC:

17555

AN:

1111962

Other (OTH)

AF:

0.0125

AC:

757

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1097

2193

3290

4386

5483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0106

AC:

1608

AN:

152300

Hom.:

Cov.:

AF XY:

0.00965

AC XY:

719

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00294

AC:

122

AN:

41556

American (AMR)

AF:

0.00628

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00914

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0175

AC:

1189

AN:

68024

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.00962

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 29, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

819+G>C in intron 10 of USH1C: This variant is not expected to have clinical sig nificance because it has been identified in 1.7% (122/7020) of European American chromosomes and 0.1% (4/3738) of African American chromosomes from a broad popu lation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs41282936). -

May 12, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 1C

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

(source)

DANN

Benign

0.73

PhyloP100

-0.33

Mutation Taster

=100/0

polymorphism

(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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rs41282936

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