11-17509510-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The ENST00000005226.12(USH1C):c.1859G>A(p.Arg620His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 581,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R620C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000057 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

USH1C
ENST00000005226.12 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.34

Publications

7 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15667033).

BP6

Variant 11-17509510-C-T is Benign according to our data. Variant chr11-17509510-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 763794.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000005226.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	NM_153676.4	MANE Select	c.1859G>A	p.Arg620His	missense	Exon 18 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7530G>A		intron	N/A	NP_005700.2
USH1C	NM_001440679.1		c.1470+2392G>A		intron	N/A	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1859G>A	p.Arg620His	missense	Exon 18 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7530G>A		intron	N/A	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.1228-7530G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes

AF:

0.0000568

AC:

AN:

35216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000192

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000306

AC:

AN:

228446

AF XY:

0.0000403

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000192

Gnomad FIN exome

AF:

0.0000984

Gnomad NFE exome

AF:

0.00000942

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

546584

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

279172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16636

American (AMR)

AF:

0.00

AC:

AN:

30084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10910

East Asian (EAS)

AF:

0.000557

AC:

AN:

10764

South Asian (SAS)

AF:

0.00

AC:

AN:

46198

European-Finnish (FIN)

AF:

0.0000795

AC:

AN:

25162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2974

European-Non Finnish (NFE)

AF:

0.0000104

AC:

AN:

383108

Other (OTH)

AF:

0.00

AC:

AN:

20748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000568

AC:

AN:

35216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

16794

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

10418

American (AMR)

AF:

0.00

AC:

AN:

2494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

918

East Asian (EAS)

AF:

0.00

AC:

AN:

1588

South Asian (SAS)

AF:

0.00

AC:

AN:

1032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

16976

Other (OTH)

AF:

0.00

AC:

AN:

416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.035

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.71

M_CAP

Benign

0.038

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.29

REVEL

Benign

0.060

Sift

Benign

0.33

Sift4G

Benign

0.28

Vest4

0.32

MutPred

0.39

Loss of solvent accessibility (P = 6e-04)

MVP

0.47

MPC

0.076

ClinPred

0.15

GERP RS

5.9

gMVP

0.22

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over