11-17521006-C-T

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.1086-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,613,244 control chromosomes in the GnomAD database, including 3,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 909 hom., cov: 31)

Exomes 𝑓: 0.046 ( 2180 hom. )

Consequence

USH1C
NM_153676.4 intron

Scores

Splicing: ADA: 0.00004067

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.118

Publications

10 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=-0.59).

BP6

Variant 11-17521006-C-T is Benign according to our data. Variant chr11-17521006-C-T is described in ClinVar as Benign. ClinVar VariationId is 47974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.1086-12G>A		intron_variant	Intron 13 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 link	c.1086-12G>A		intron_variant	Intron 13 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.1086-12G>A		intron_variant	Intron 13 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9 link	c.1086-12G>A		intron_variant	Intron 13 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes

AF:

0.0861

AC:

13084

AN:

152014

Hom.:

897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0881

Gnomad ASJ

AF:

0.0859

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.0208

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0402

Gnomad OTH

AF:

0.0852

GnomAD2 exomes

AF:

0.0603

AC:

15159

AN:

251444

AF XY:

0.0550

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0919

Gnomad EAS exome

AF:

0.0313

Gnomad FIN exome

AF:

0.0369

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0634

GnomAD4 exome

AF:

0.0465

AC:

67897

AN:

1461112

Hom.:

2180

Cov.:

AF XY:

0.0454

AC XY:

33004

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.196

AC:

6564

AN:

33432

American (AMR)

AF:

0.101

AC:

4534

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0869

AC:

2270

AN:

26132

East Asian (EAS)

AF:

0.0364

AC:

1445

AN:

39694

South Asian (SAS)

AF:

0.0277

AC:

2393

AN:

86252

European-Finnish (FIN)

AF:

0.0404

AC:

2153

AN:

53350

Middle Eastern (MID)

AF:

0.0807

AC:

465

AN:

5764

European-Non Finnish (NFE)

AF:

0.0402

AC:

44651

AN:

1111392

Other (OTH)

AF:

0.0567

AC:

3422

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

3295

6590

9885

13180

16475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1804

3608

5412

7216

9020

<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:

0.0864

AC:

13138

AN:

152132

Hom.:

909

Cov.:

AF XY:

0.0843

AC XY:

6271

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.191

AC:

7910

AN:

41452

American (AMR)

AF:

0.0881

AC:

1346

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0859

AC:

298

AN:

3470

East Asian (EAS)

AF:

0.0316

AC:

164

AN:

5182

South Asian (SAS)

AF:

0.0206

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0364

AC:

386

AN:

10608

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0402

AC:

2733

AN:

68006

Other (OTH)

AF:

0.0844

AC:

178

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

550

1099

1649

2198

2748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0562

Hom.:

201

Bravo

AF:

0.0964

Asia WGS

AF:

0.0420

AC:

144

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 30, 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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Usher syndrome type 1C

Benign:2

Jan 13, 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

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000041

dbscSNV1_RF

Benign

0.060

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

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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