11-17522838-C-G

Variant names:

• chr11-17522838-C-G
• NM_153676.4:c.965G>C

Variant summary

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

The NM_153676.4(USH1C):​c.965G>C​(p.Arg322Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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.965G>C	p.Arg322Pro	missense_variant	Exon 12 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.965G>C	p.Arg322Pro	missense_variant	Exon 12 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.965G>C	p.Arg322Pro	missense_variant	Exon 12 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.965G>C	p.Arg322Pro	missense_variant	Exon 12 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;.
Eigen	Benign	-0.00044
Eigen_PC	Benign	-0.0079
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L;.;.;L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;D;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.97	D;.;D;.
Vest4		0.61
MutPred		0.38		Loss of MoRF binding (P = 0.0024);.;.;Loss of MoRF binding (P = 0.0024);
MVP		0.51
MPC		0.18
ClinPred		0.88	D
GERP RS		3.1
Varity_R		0.61
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17544385;