11-17531460-G-C

Variant summary

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

The NM_153676.4(USH1C):c.187C>G(p.Arg63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R63Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71

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/exons	MANE	UniProt
USH1C	NM_153676.4	c.187C>G	p.Arg63Gly	missense_variant	3/27	ENST00000005226.12
USH1C	NM_005709.4	c.187C>G	p.Arg63Gly	missense_variant	3/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.187C>G	p.Arg63Gly	missense_variant	3/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.187C>G	p.Arg63Gly	missense_variant	3/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.024	D;D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.95
MutPred		0.64		Gain of catalytic residue at I62 (P = 0.1298);.;Gain of catalytic residue at I62 (P = 0.1298);Gain of catalytic residue at I62 (P = 0.1298);.;
MVP		0.61
MPC		0.43
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.54
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs375741564; hg19: chr11-17553007;