rs2072225

Variant names:

• chr11-17494423-G-A
• rs2072225
• NM_153676.4:c.2656-47C>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.2656-47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,562,516 control chromosomes in the GnomAD database, including 134,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11170 hom., cov: 33)
  • Exomes 𝑓: 0.42 (123422 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0590

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=-0.85).
• BP6: Variant 11-17494423-G-A is Benign according to our data. Variant chr11-17494423-G-A is described in ClinVar as [Benign]. Clinvar id is 262733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2656-47C>T		intron_variant	Intron 26 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1647-47C>T		intron_variant	Intron 20 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2656-47C>T		intron_variant	Intron 26 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1647-47C>T		intron_variant	Intron 20 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57459 AN: 152010 Hom.: 11167 Cov.: 33

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.389

GnomAD3 exomes AF: 0.379 AC: 66780 AN: 176376 Hom.: 12993 AF XY: 0.381 AC XY: 35887 AN XY: 94160

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.415 AC: 585779 AN: 1410388 Hom.: 123422 Cov.: 30 AF XY: 0.413 AC XY: 287933 AN XY: 697430

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.430

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.435

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.378 AC: 57472 AN: 152128 Hom.: 11170 Cov.: 33 AF XY: 0.378 AC XY: 28103 AN XY: 74340

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.442

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.387

Alfa AF: 0.395 Hom.: 3036

Bravo AF: 0.368

Asia WGS AF: 0.305 AC: 1062 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1C Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2072225; hg19: chr11-17515970; COSMIC: COSV50019792;