NM_153676.4:c.2656-47C>T

Variant names:

• chr11-17494423-G-A
• rs2072225
• NM_153676.4:c.2656-47C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.379 AC: 66780 AN: 176376 AF XY: 0.381

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 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

African (AFR) AF: 0.300 AC: 9652 AN: 32184

American (AMR) AF: 0.303 AC: 11491 AN: 37952

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 10911 AN: 25380

East Asian (EAS) AF: 0.301 AC: 11171 AN: 37124

South Asian (SAS) AF: 0.310 AC: 24940 AN: 80364

European-Finnish (FIN) AF: 0.423 AC: 21230 AN: 50226

Middle Eastern (MID) AF: 0.323 AC: 1757 AN: 5436

European-Non Finnish (NFE) AF: 0.435 AC: 471261 AN: 1083254

Other (OTH) AF: 0.400 AC: 23366 AN: 58468

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

African (AFR) AF: 0.307 AC: 12764 AN: 41512

American (AMR) AF: 0.334 AC: 5111 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1534 AN: 3472

East Asian (EAS) AF: 0.292 AC: 1506 AN: 5160

South Asian (SAS) AF: 0.305 AC: 1474 AN: 4826

European-Finnish (FIN) AF: 0.442 AC: 4671 AN: 10568

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29119 AN: 67976

Other (OTH) AF: 0.387 AC: 817 AN: 2110

Alfa AF: 0.391 Hom.: 6489

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

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		0.059
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072225; hg19: chr11-17515970; COSMIC: COSV50019792;