11-17498150-C-G

Variant names:

• chr11-17498150-C-G
• rs2072232
• NM_153676.4:c.2490+12G>C

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.2490+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,610,522 control chromosomes in the GnomAD database, including 10,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1183 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9640 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.173
• 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 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 11-17498150-C-G is Benign according to our data. Variant chr11-17498150-C-G is described in ClinVar as Benign. ClinVar VariationId is 48006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.2490+12G>C		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1590+12G>C		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1776+12G>C		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.2490+12G>C		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1590+12G>C		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1533+12G>C		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17161 AN: 152032 Hom.: 1178 Cov.: 33

Gnomad AFR AF: 0.0973

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.124 AC: 31172 AN: 250950 AF XY: 0.122

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.0632

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.106 AC: 154950 AN: 1458370 Hom.: 9640 Cov.: 29 AF XY: 0.107 AC XY: 77609 AN XY: 725712

African (AFR) AF: 0.0975 AC: 3259 AN: 33426

American (AMR) AF: 0.159 AC: 7126 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3835 AN: 26116

East Asian (EAS) AF: 0.300 AC: 11897 AN: 39688

South Asian (SAS) AF: 0.114 AC: 9790 AN: 86176

European-Finnish (FIN) AF: 0.0666 AC: 3559 AN: 53402

Middle Eastern (MID) AF: 0.187 AC: 1078 AN: 5766

European-Non Finnish (NFE) AF: 0.0965 AC: 107003 AN: 1108804

Other (OTH) AF: 0.123 AC: 7403 AN: 60276

GnomAD4 genome AF: 0.113 AC: 17184 AN: 152152 Hom.: 1183 Cov.: 33 AF XY: 0.114 AC XY: 8501 AN XY: 74380

African (AFR) AF: 0.0975 AC: 4047 AN: 41520

American (AMR) AF: 0.170 AC: 2590 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 543 AN: 3468

East Asian (EAS) AF: 0.304 AC: 1568 AN: 5152

South Asian (SAS) AF: 0.119 AC: 572 AN: 4816

European-Finnish (FIN) AF: 0.0613 AC: 650 AN: 10598

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6804 AN: 68004

Other (OTH) AF: 0.131 AC: 277 AN: 2112

Alfa AF: 0.0731 Hom.: 112

Bravo AF: 0.121

Asia WGS AF: 0.204 AC: 707 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 1C (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		-0.17
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: rs2072232; hg19: chr11-17519697; COSMIC: COSV50026168; COSMIC: COSV50026168;