11-17504709-A-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.2134-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,541,542 control chromosomes in the GnomAD database, including 2,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 233 hom., cov: 33)

Exomes 𝑓: 0.067 ( 2553 hom. )

Consequence

USH1C
NM_153676.4 intron

Scores

Splicing: ADA: 0.0002548

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.638

Publications

2 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=-0.86).

BP6

Variant 11-17504709-A-G is Benign according to our data. Variant chr11-17504709-A-G is described in ClinVar as Benign. ClinVar VariationId is 47989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.2134-12T>C		intron_variant	Intron 19 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 link	c.1285-2729T>C		intron_variant	Intron 15 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.2134-12T>C		intron_variant	Intron 19 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9 link	c.1285-2729T>C		intron_variant	Intron 15 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7454

AN:

150088

Hom.:

234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.0396

Gnomad AMR

AF:

0.0558

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0549

Gnomad FIN

AF:

0.0430

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0713

Gnomad OTH

AF:

0.0634

GnomAD2 exomes

AF:

0.133

AC:

13967

AN:

104990

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.216

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.100

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.0665

AC:

92585

AN:

1391358

Hom.:

2553

Cov.:

AF XY:

0.0671

AC XY:

46470

AN XY:

692852

show subpopulations

African (AFR)

AF:

0.0112

AC:

357

AN:

31830

American (AMR)

AF:

0.0423

AC:

1818

AN:

42940

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2638

AN:

25160

East Asian (EAS)

AF:

0.000185

AC:

AN:

37776

South Asian (SAS)

AF:

0.0567

AC:

4715

AN:

83140

European-Finnish (FIN)

AF:

0.0484

AC:

2451

AN:

50678

Middle Eastern (MID)

AF:

0.102

AC:

572

AN:

5602

European-Non Finnish (NFE)

AF:

0.0722

AC:

76256

AN:

1056618

Other (OTH)

AF:

0.0655

AC:

3771

AN:

57614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

4498

8995

13493

17990

22488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2758

5516

8274

11032

13790

<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:

0.0496

AC:

7451

AN:

150184

Hom.:

233

Cov.:

AF XY:

0.0482

AC XY:

3536

AN XY:

73338

show subpopulations

African (AFR)

AF:

0.0134

AC:

549

AN:

41082

American (AMR)

AF:

0.0556

AC:

838

AN:

15066

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

357

AN:

3440

East Asian (EAS)

AF:

0.000388

AC:

AN:

5150

South Asian (SAS)

AF:

0.0548

AC:

261

AN:

4762

European-Finnish (FIN)

AF:

0.0430

AC:

439

AN:

10198

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0713

AC:

4793

AN:

67200

Other (OTH)

AF:

0.0629

AC:

131

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

362

723

1085

1446

1808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0564

Hom.:

Bravo

AF:

0.0473

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

2134-12T>C in intron 21 of USH1C: This variant is not expected to have clinical significance because it has been identified in 7.7% (524/7020) of European Ameri can chromosomes and 1.7% (62/3738) of African American chromosomes in a broad po pulation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS /; dbSNP rs76769358). -

May 08, 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. -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 1C

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

-0.86

CADD

Benign

0.74

(source)

DANN

Benign

0.54

PhyloP100

-0.64

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.0

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