11-17509546-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153676.4(USH1C):c.1823C>G(p.Pro608Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000692 in 1,602,700 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P608L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00070 ( 1 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:2

Conservation

PhyloP100: 4.44

Publications

12 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 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
Usher syndrome type 1
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18056676).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH1C	NM_153676.4	MANE Select	c.1823C>G	p.Pro608Arg	missense	Exon 18 of 27	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7566C>G		intron	N/A	NP_005700.2	A0A0S2Z4U9
USH1C	NM_001440679.1		c.1470+2356C>G		intron	N/A	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1823C>G	p.Pro608Arg	missense	Exon 18 of 27	ENSP00000005226.7	Q9Y6N9-5
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7566C>G		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
USH1C	ENST00000527020.5	TSL:1	c.1228-7566C>G		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes

AF:

0.000593

AC:

AN:

151748

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000486

AC:

117

AN:

240790

AF XY:

0.000444

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000440

Gnomad ASJ exome

AF:

0.000416

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000818

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000702

AC:

1019

AN:

1450952

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

475

AN XY:

720514

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33364

American (AMR)

AF:

0.000473

AC:

AN:

44406

Ashkenazi Jewish (ASJ)

AF:

0.000271

AC:

AN:

25818

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.000118

AC:

AN:

84922

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

51682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.000850

AC:

940

AN:

1105544

Other (OTH)

AF:

0.000567

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.577

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000593

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

AN XY:

74062

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41300

American (AMR)

AF:

0.000723

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00102

AC:

AN:

67960

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.573

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:

0.000718

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000470

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Usher syndrome type 1C (2)

Autosomal recessive nonsyndromic hearing loss 18A (1)

Meniere disease (1)

not specified (1)

Optic atrophy (1)

Retinal dystrophy (1)

Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.93

PhyloP100

4.4

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

REVEL

Benign

0.20

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.53

MVP

0.60

MPC

0.31

ClinPred

0.12

GERP RS

5.8

gMVP

0.35

Mutation Taster

=34/66

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over