rs2190454

chr11-17512088-G-Achr11-17512088-G-Cchr11-17512088-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):c.1261-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,611,520 control chromosomes in the GnomAD database, including 393,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37318 hom., cov: 32)
  • Exomes 𝑓: 0.70 (356530 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0700

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-17512088-G-A is Benign according to our data. Variant chr11-17512088-G-A is described in ClinVar as [Benign]. Clinvar id is 670417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17512088-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.1284+5313C>T		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.1261-34C>T		intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.1261-34C>T		intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.1284+5313C>T		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106436 AN: 151962 Hom.: 37285 Cov.: 32

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.752

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.717 AC: 179728 AN: 250676 Hom.: 64961 AF XY: 0.715 AC XY: 96949 AN XY: 135640

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.703

Gnomad SAS exome AF: 0.790

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.698 AC: 1018019 AN: 1459440 Hom.: 356530 Cov.: 35 AF XY: 0.700 AC XY: 508188 AN XY: 726258

Gnomad4 AFR exome AF: 0.692

Gnomad4 AMR exome AF: 0.805

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.721

Gnomad4 SAS exome AF: 0.788

Gnomad4 FIN exome AF: 0.715

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.691

GnomAD4 genome AF: 0.700 AC: 106521 AN: 152080 Hom.: 37318 Cov.: 32 AF XY: 0.704 AC XY: 52378 AN XY: 74354

Gnomad4 AFR AF: 0.692

Gnomad4 AMR AF: 0.752

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.796

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.689

Gnomad4 OTH AF: 0.686

Alfa AF: 0.683 Hom.: 20423

Bravo AF: 0.699

Asia WGS AF: 0.769 AC: 2676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 1C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.7
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2190454; hg19: chr11-17533635;