NM_153676.4:c.1085+21C>G

Variant names:

• chr11-17521325-G-C
• rs2240488
• NM_153676.4:c.1085+21C>G

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.1085+21C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,611,358 control chromosomes in the GnomAD database, including 182,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14402 hom., cov: 32)
  • Exomes 𝑓: 0.48 (168105 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.38
• Publications: 14 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=-0.86).
• BP6: Variant 11-17521325-G-C is Benign according to our data. Variant chr11-17521325-G-C is described in ClinVar as Benign. ClinVar VariationId is 47973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.1085+21C>G		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1085+21C>G		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1118+21C>G		intron	N/A	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1085+21C>G		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1085+21C>G		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1028+21C>G		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64906 AN: 151872 Hom.: 14390 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.468 AC: 117633 AN: 251476 AF XY: 0.467

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.477 AC: 695465 AN: 1459368 Hom.: 168105 Cov.: 35 AF XY: 0.476 AC XY: 345728 AN XY: 726156

African (AFR) AF: 0.283 AC: 9472 AN: 33426

American (AMR) AF: 0.494 AC: 22080 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10906 AN: 26118

East Asian (EAS) AF: 0.634 AC: 25143 AN: 39678

South Asian (SAS) AF: 0.454 AC: 39129 AN: 86220

European-Finnish (FIN) AF: 0.440 AC: 23500 AN: 53412

Middle Eastern (MID) AF: 0.345 AC: 1990 AN: 5764

European-Non Finnish (NFE) AF: 0.482 AC: 535230 AN: 1109694

Other (OTH) AF: 0.464 AC: 28015 AN: 60334

GnomAD4 genome AF: 0.427 AC: 64943 AN: 151990 Hom.: 14402 Cov.: 32 AF XY: 0.430 AC XY: 31939 AN XY: 74282

African (AFR) AF: 0.296 AC: 12291 AN: 41466

American (AMR) AF: 0.462 AC: 7062 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1472 AN: 3472

East Asian (EAS) AF: 0.627 AC: 3235 AN: 5162

South Asian (SAS) AF: 0.464 AC: 2232 AN: 4808

European-Finnish (FIN) AF: 0.432 AC: 4568 AN: 10566

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32561 AN: 67942

Other (OTH) AF: 0.417 AC: 875 AN: 2100

Alfa AF: 0.379 Hom.: 1795

Bravo AF: 0.423

Asia WGS AF: 0.528 AC: 1833 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1C Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.040
DANN	Benign	0.45
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2240488; hg19: chr11-17542872; COSMIC: COSV107202851; COSMIC: COSV107202851;