rs2240489

Variant names:

• chr11-17533367-G-C
• rs2240489
• ENST00000527720.5:c.-102C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-17533367-G-C
• chr11-17533367-G-A
• chr11-17533367-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000527720.5(USH1C):​c.-102C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,379,248 control chromosomes in the GnomAD database, including 202,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (23430 hom., cov: 28)
  • Exomes 𝑓: 0.54 (178797 hom.)
• Consequence: USH1C ENST00000527720.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.38
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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=-0.96).
• BP6: Variant 11-17533367-G-C is Benign according to our data. Variant chr11-17533367-G-C is described in ClinVar as Benign. ClinVar VariationId is 262734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000527720.5. 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.37-45C>G		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.37-45C>G		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.70-45C>G		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000527720.5	TSL:1	c.-102C>G		5_prime_UTR	Exon 1 of 20	ENSP00000432944.1	Q9Y6N9-2
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.37-45C>G		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.37-45C>G		intron	N/A	ENSP00000317018.4	Q9Y6N9-1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 82868 AN: 146130 Hom.: 23409 Cov.: 28

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.540 AC: 123874 AN: 229536 AF XY: 0.541

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.556

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.535 AC: 659945 AN: 1233008 Hom.: 178797 Cov.: 17 AF XY: 0.537 AC XY: 335195 AN XY: 624320

African (AFR) AF: 0.636 AC: 17659 AN: 27750

American (AMR) AF: 0.495 AC: 21534 AN: 43474

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 13697 AN: 24598

East Asian (EAS) AF: 0.573 AC: 21668 AN: 37812

South Asian (SAS) AF: 0.589 AC: 48245 AN: 81880

European-Finnish (FIN) AF: 0.601 AC: 27485 AN: 45700

Middle Eastern (MID) AF: 0.578 AC: 2992 AN: 5174

European-Non Finnish (NFE) AF: 0.523 AC: 477754 AN: 914152

Other (OTH) AF: 0.551 AC: 28911 AN: 52468

GnomAD4 genome AF: 0.567 AC: 82928 AN: 146240 Hom.: 23430 Cov.: 28 AF XY: 0.569 AC XY: 40382 AN XY: 71026

African (AFR) AF: 0.632 AC: 24361 AN: 38544

American (AMR) AF: 0.530 AC: 7888 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1918 AN: 3440

East Asian (EAS) AF: 0.566 AC: 2790 AN: 4932

South Asian (SAS) AF: 0.587 AC: 2783 AN: 4738

European-Finnish (FIN) AF: 0.627 AC: 5907 AN: 9418

Middle Eastern (MID) AF: 0.577 AC: 164 AN: 284

European-Non Finnish (NFE) AF: 0.532 AC: 35648 AN: 67056

Other (OTH) AF: 0.558 AC: 1142 AN: 2046

Alfa AF: 0.324 Hom.: 625

Bravo AF: 0.581

ClinVar

ClinVar submissions

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	-0.96
CADD	Benign	0.15
DANN	Benign	0.34
PhyloP100		-2.4
PromoterAI		-0.022	Neutral
Mutation Taster		=300/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2240489;

hg19: chr11-17554914;

COSMIC: COSV50014857;