rs770543827

Positions:

• chr11-17526423-C-A
• chr11-17526423-C-G
• chr11-17526423-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 13/21 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23365194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.598G>T	p.Gly200Cys	missense_variant	8/27	ENST00000005226.12
USH1C	NM_005709.4	c.598G>T	p.Gly200Cys	missense_variant	8/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.598G>T	p.Gly200Cys	missense_variant	8/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.598G>T	p.Gly200Cys	missense_variant	8/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;L;L;.
MutationTaster	Benign	0.58	D;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N;N;N;N;D
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;.
Polyphen		0.68	P;.;P;.;.
Vest4		0.41
MutPred		0.32		Loss of phosphorylation at S201 (P = 0.0679);.;Loss of phosphorylation at S201 (P = 0.0679);Loss of phosphorylation at S201 (P = 0.0679);.;
MVP		0.48
MPC		0.18
ClinPred		0.73	D
GERP RS		1.5
Varity_R		0.20
gMVP		0.68

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: rs770543827; hg19: chr11-17547970;