rs2190454

Variant names:

• chr11-17512088-G-A
• rs2190454
• NM_153676.4:c.1261-34C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17512088-G-A
• chr11-17512088-G-C
• chr11-17512088-G-T

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.1261-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,611,520 control chromosomes in the GnomAD database, including 393,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37318 hom., cov: 32)
  • Exomes 𝑓: 0.70 (356530 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0700
• Publications: 17 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=-0.84).
• BP6: Variant 11-17512088-G-A is Benign according to our data. Variant chr11-17512088-G-A is described in ClinVar as Benign. ClinVar VariationId is 670417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.775 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.1261-34C>T		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1284+5313C>T		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1318-34C>T		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.1261-34C>T		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+5313C>T		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1227+5313C>T		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106436 AN: 151962 Hom.: 37285 Cov.: 32

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.752

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.717 AC: 179728 AN: 250676 AF XY: 0.715

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.698 AC: 1018019 AN: 1459440 Hom.: 356530 Cov.: 35 AF XY: 0.700 AC XY: 508188 AN XY: 726258

African (AFR) AF: 0.692 AC: 23125 AN: 33422

American (AMR) AF: 0.805 AC: 35980 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15670 AN: 26128

East Asian (EAS) AF: 0.721 AC: 28632 AN: 39690

South Asian (SAS) AF: 0.788 AC: 67914 AN: 86216

European-Finnish (FIN) AF: 0.715 AC: 37798 AN: 52842

Middle Eastern (MID) AF: 0.630 AC: 3633 AN: 5764

European-Non Finnish (NFE) AF: 0.688 AC: 763601 AN: 1110356

Other (OTH) AF: 0.691 AC: 41666 AN: 60304

GnomAD4 genome AF: 0.700 AC: 106521 AN: 152080 Hom.: 37318 Cov.: 32 AF XY: 0.704 AC XY: 52378 AN XY: 74354

African (AFR) AF: 0.692 AC: 28709 AN: 41468

American (AMR) AF: 0.752 AC: 11483 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2090 AN: 3470

East Asian (EAS) AF: 0.714 AC: 3695 AN: 5174

South Asian (SAS) AF: 0.796 AC: 3833 AN: 4814

European-Finnish (FIN) AF: 0.716 AC: 7582 AN: 10588

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.689 AC: 46827 AN: 67976

Other (OTH) AF: 0.686 AC: 1450 AN: 2114

Alfa AF: 0.685 Hom.: 26687

Bravo AF: 0.699

Asia WGS AF: 0.769 AC: 2676 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	Usher syndrome type 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.40
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2190454; hg19: chr11-17533635;