11-17509546-G-T

Position:

• chr11-17509546-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_153676.4(USH1C):​c.1823C>A​(p.Pro608Gln) variant causes a missense change. 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. P608R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44

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]

USH1C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17509546-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1823C>A	p.Pro608Gln	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-7566C>A		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1823C>A	p.Pro608Gln	missense_variant	18/27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1285-7566C>A		intron_variant		1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450950 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 720512

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.51
MutPred		0.38		Loss of glycosylation at P608 (P = 0.0057);
MVP		0.59
MPC		0.31
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs41282932; hg19: chr11-17531093;