Genetic Variant USH1C:p.Gly200Cys (chr11-17526423-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153676.4(USH1C):c.598G>T(p.Gly200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G200S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23365194).

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
USH1C	NM_153676.4	MANE Select	c.598G>T	p.Gly200Cys	missense	Exon 8 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.598G>T	p.Gly200Cys	missense	Exon 8 of 21	NP_005700.2
USH1C	NM_001440679.1		c.631G>T	p.Gly211Cys	missense	Exon 8 of 22	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.598G>T	p.Gly200Cys	missense	Exon 8 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.598G>T	p.Gly200Cys	missense	Exon 8 of 21	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.598G>T	p.Gly200Cys	missense	Exon 8 of 20	ENSP00000436934.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251082

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

M_CAP

Benign

0.026

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

2.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.3

REVEL

Benign

0.13

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.011

Polyphen

0.68

Vest4

0.41

MutPred

0.32

Loss of phosphorylation at S201 (P = 0.0679)

MVP

0.48

MPC

0.18

ClinPred

0.73

GERP RS

1.5

Varity_R

0.20

gMVP

0.68

Mutation Taster

=79/21

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over