rs41282936

Variant names:

• chr11-17523409-C-G
• rs41282936
• NM_153676.4:c.819+10G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-17523409-C-G
• chr11-17523409-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):​c.819+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,136 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.014 (164 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.326
• Publications: 6 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=-0.78).
• BP6: Variant 11-17523409-C-G is Benign according to our data. Variant chr11-17523409-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1608/152300) while in subpopulation NFE AF = 0.0175 (1189/68024). AF 95% confidence interval is 0.0167. There are 17 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,Unknown gene

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.819+10G>C		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.819+10G>C		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.852+10G>C		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.819+10G>C		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.819+10G>C		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.819+10G>C		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1608 AN: 152182 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0107 AC: 2689 AN: 251442 AF XY: 0.0104

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0136 AC: 19859 AN: 1461836 Hom.: 164 Cov.: 33 AF XY: 0.0133 AC XY: 9705 AN XY: 727214

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00523 AC: 234 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 540 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86252

European-Finnish (FIN) AF: 0.0118 AC: 630 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0158 AC: 17555 AN: 1111962

Other (OTH) AF: 0.0125 AC: 757 AN: 60396

GnomAD4 genome AF: 0.0106 AC: 1608 AN: 152300 Hom.: 17 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74480

African (AFR) AF: 0.00294 AC: 122 AN: 41556

American (AMR) AF: 0.00628 AC: 96 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1189 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0175 Hom.: 4

Bravo AF: 0.00962

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 1C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism

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: rs41282936; hg19: chr11-17544956; COSMIC: COSV50014818; COSMIC: COSV50014818;