rs2072227

Variant names:

• chr11-17494491-C-T
• rs2072227
• NM_153676.4:c.2656-115G>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.2656-115G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,219,194 control chromosomes in the GnomAD database, including 126,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14718 hom., cov: 33)
  • Exomes 𝑓: 0.45 (112135 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.441
• Publications: 2 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 11-17494491-C-T is Benign according to our data. Variant chr11-17494491-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2656-115G>A		intron_variant	Intron 26 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1647-115G>A		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.2656-115G>A		intron_variant	Intron 26 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1647-115G>A		intron_variant	Intron 20 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66198 AN: 151958 Hom.: 14708 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.453 AC: 483428 AN: 1067118 Hom.: 112135 Cov.: 14 AF XY: 0.451 AC XY: 243920 AN XY: 540788

African (AFR) AF: 0.407 AC: 10191 AN: 25010

American (AMR) AF: 0.325 AC: 11416 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 10903 AN: 22960

East Asian (EAS) AF: 0.304 AC: 10331 AN: 34016

South Asian (SAS) AF: 0.376 AC: 27225 AN: 72480

European-Finnish (FIN) AF: 0.474 AC: 22883 AN: 48314

Middle Eastern (MID) AF: 0.374 AC: 1433 AN: 3828

European-Non Finnish (NFE) AF: 0.473 AC: 368263 AN: 778452

Other (OTH) AF: 0.443 AC: 20783 AN: 46908

GnomAD4 genome AF: 0.436 AC: 66237 AN: 152076 Hom.: 14718 Cov.: 33 AF XY: 0.435 AC XY: 32349 AN XY: 74340

African (AFR) AF: 0.412 AC: 17081 AN: 41474

American (AMR) AF: 0.367 AC: 5614 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3466

East Asian (EAS) AF: 0.294 AC: 1516 AN: 5152

South Asian (SAS) AF: 0.376 AC: 1809 AN: 4816

European-Finnish (FIN) AF: 0.487 AC: 5163 AN: 10592

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31960 AN: 67952

Other (OTH) AF: 0.432 AC: 911 AN: 2110

Alfa AF: 0.456 Hom.: 10204

Bravo AF: 0.425

Asia WGS AF: 0.351 AC: 1221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jul 07, 2018

GeneDx

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	-0.79
CADD	Benign	7.5
DANN	Benign	0.55
PhyloP100		0.44
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: rs2072227; hg19: chr11-17516038;