11-17498317-C-T

Variant names:

• chr11-17498317-C-T
• rs2072233
• NM_153676.4:c.2381-46G>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.2381-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,574,396 control chromosomes in the GnomAD database, including 10,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1150 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9298 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.47
• 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=-0.88).
• BP6: Variant 11-17498317-C-T is Benign according to our data. Variant chr11-17498317-C-T is described in ClinVar as Benign. ClinVar VariationId is 262732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 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.2381-46G>A		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1481-46G>A		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1667-46G>A		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.2381-46G>A		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1481-46G>A		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1424-46G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16831 AN: 152018 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.122 AC: 30702 AN: 251016 AF XY: 0.120

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.0629

Gnomad NFE exome AF: 0.0993

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.105 AC: 149521 AN: 1422260 Hom.: 9298 Cov.: 24 AF XY: 0.106 AC XY: 75088 AN XY: 709866

African (AFR) AF: 0.0914 AC: 2987 AN: 32694

American (AMR) AF: 0.158 AC: 7047 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3721 AN: 25876

East Asian (EAS) AF: 0.293 AC: 11584 AN: 39488

South Asian (SAS) AF: 0.110 AC: 9418 AN: 85484

European-Finnish (FIN) AF: 0.0664 AC: 3542 AN: 53312

Middle Eastern (MID) AF: 0.185 AC: 1051 AN: 5686

European-Non Finnish (NFE) AF: 0.0956 AC: 102829 AN: 1076022

Other (OTH) AF: 0.124 AC: 7342 AN: 59034

GnomAD4 genome AF: 0.111 AC: 16855 AN: 152136 Hom.: 1150 Cov.: 32 AF XY: 0.113 AC XY: 8371 AN XY: 74380

African (AFR) AF: 0.0917 AC: 3804 AN: 41504

American (AMR) AF: 0.170 AC: 2597 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 535 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1577 AN: 5168

South Asian (SAS) AF: 0.115 AC: 553 AN: 4810

European-Finnish (FIN) AF: 0.0613 AC: 650 AN: 10596

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.0987 AC: 6714 AN: 67990

Other (OTH) AF: 0.134 AC: 284 AN: 2112

Alfa AF: 0.113 Hom.: 683

Bravo AF: 0.118

Asia WGS AF: 0.212 AC: 737 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.010
DANN	Benign	0.77
PhyloP100		-3.5
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: rs2072233; hg19: chr11-17519864; COSMIC: COSV50026183; COSMIC: COSV50026183;