11-17531402-G-C

Variant names:

• chr11-17531402-G-C
• rs769021971
• NM_153676.4:c.245C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153676.4(USH1C):​c.245C>G​(p.Ser82Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.245C>G	p.Ser82Cys	missense_variant	Exon 3 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.245C>G	p.Ser82Cys	missense_variant	Exon 3 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.245C>G	p.Ser82Cys	missense_variant	Exon 3 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.245C>G	p.Ser82Cys	missense_variant	Exon 3 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727018

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

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 Cov.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser82Cys variant in USH1C has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Ser82Cys variant is uncer tain. -

Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1

Nov 26, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1C Uncertain:1

Dec 30, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.84
MutPred		0.40		Loss of phosphorylation at S82 (P = 0.005);.;Loss of phosphorylation at S82 (P = 0.005);Loss of phosphorylation at S82 (P = 0.005);.;
MVP		0.58
MPC		0.38
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs769021971; hg19: chr11-17552949;