11-17526468-C-T

Variant names:

• chr11-17526468-C-T
• rs6486378
• NM_153676.4:c.580-27G>A

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.580-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,603,294 control chromosomes in the GnomAD database, including 72,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7036 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65136 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.974
• Publications: 11 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=-0.79).
• BP6: Variant 11-17526468-C-T is Benign according to our data. Variant chr11-17526468-C-T is described in ClinVar as Benign. ClinVar VariationId is 262738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 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.580-27G>A		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.580-27G>A		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.613-27G>A		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.580-27G>A		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.580-27G>A		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.580-27G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45959 AN: 151994 Hom.: 7028 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.308

GnomAD2 exomes AF: 0.313 AC: 76142 AN: 243178 AF XY: 0.309

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.296

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.297 AC: 430672 AN: 1451180 Hom.: 65136 Cov.: 29 AF XY: 0.295 AC XY: 213237 AN XY: 722352

African (AFR) AF: 0.295 AC: 9820 AN: 33268

American (AMR) AF: 0.349 AC: 15426 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7821 AN: 26014

East Asian (EAS) AF: 0.515 AC: 20379 AN: 39576

South Asian (SAS) AF: 0.268 AC: 22966 AN: 85744

European-Finnish (FIN) AF: 0.289 AC: 15210 AN: 52660

Middle Eastern (MID) AF: 0.300 AC: 1725 AN: 5750

European-Non Finnish (NFE) AF: 0.289 AC: 319161 AN: 1103928

Other (OTH) AF: 0.303 AC: 18164 AN: 60032

GnomAD4 genome AF: 0.302 AC: 45977 AN: 152114 Hom.: 7036 Cov.: 33 AF XY: 0.301 AC XY: 22384 AN XY: 74354

African (AFR) AF: 0.293 AC: 12140 AN: 41482

American (AMR) AF: 0.324 AC: 4964 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2580 AN: 5146

South Asian (SAS) AF: 0.268 AC: 1293 AN: 4822

European-Finnish (FIN) AF: 0.286 AC: 3029 AN: 10594

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.294 AC: 19956 AN: 67982

Other (OTH) AF: 0.306 AC: 648 AN: 2116

Alfa AF: 0.276 Hom.: 3252

Bravo AF: 0.308

Asia WGS AF: 0.352 AC: 1222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 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: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

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	-0.79
CADD	Benign	8.9
DANN	Benign	0.57
PhyloP100		0.97
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: rs6486378; hg19: chr11-17548015; COSMIC: COSV50014663;