rs148168494

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_153676.4(USH1C):ā€‹c.2194A>Gā€‹(p.Lys732Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27548912).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH1CNM_153676.4 linkuse as main transcriptc.2194A>G p.Lys732Glu missense_variant 21/27 ENST00000005226.12
USH1CNM_005709.4 linkuse as main transcriptc.1294A>G p.Lys432Glu missense_variant 16/21 ENST00000318024.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH1CENST00000005226.12 linkuse as main transcriptc.2194A>G p.Lys732Glu missense_variant 21/275 NM_153676.4 Q9Y6N9-5
USH1CENST00000318024.9 linkuse as main transcriptc.1294A>G p.Lys432Glu missense_variant 16/211 NM_005709.4 P1Q9Y6N9-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152030
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000459
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
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
251094
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461552
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727078
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152030
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74250
show subpopulations
Gnomad4 AFR
AF:
0.000459
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000389
Hom.:
0
Bravo
AF:
0.000128
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 08, 2011Variant classified as Uncertain Significance - Favor Benign. The Lys732Glu varia nt in USH1C has not been reported in the literature nor previously identified by our laboratory. However, this variant was observed in a broad population (dbSN P rs148168494) suggesting it could occur with reasonable frequency in the genera l population. Computational analyses (biochemical amino acid properties, homolog y, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against path ogenicity. In summary, the clinical significance of this variant cannot be deter mined at this time; however, based on identification of this variant in this ind ividual who has another cause for their clinical features and in dbSNP we would lean towards a more likely benign role. -
Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 24, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 03, 2022This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 432 of the USH1C protein (p.Lys432Glu). This variant is present in population databases (rs148168494, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 47994). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Usher syndrome type 1C Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jul 08, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.15
T;.;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
1.3
L;.;.;.
MutationTaster
Benign
0.98
D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.3
N;N;N;N
REVEL
Benign
0.17
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;D
Polyphen
0.88
P;.;P;.
Vest4
0.57
MVP
0.34
MPC
0.45
ClinPred
0.33
T
GERP RS
5.4
Varity_R
0.84
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148168494; hg19: chr11-17523518; API