rs45552041

Variant names:

• chr11-17527157-C-A
• rs45552041
• NM_153676.4:c.496+66G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17527157-C-A
• chr11-17527157-C-G
• chr11-17527157-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153676.4(USH1C):​c.496+66G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 0)
  • Exomes 𝑓: 0.035 (383 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0730
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17527157-C-A is Benign according to our data. Variant chr11-17527157-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 678907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.496+66G>T		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.496+66G>T		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.529+66G>T		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.496+66G>T		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.496+66G>T		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.496+66G>T		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 319 AN: 55730 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00926

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.00424

Gnomad EAS AF: 0.00233

Gnomad SAS AF: 0.00472

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.0283

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00754

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0348 AC: 16598 AN: 477172 Hom.: 383 Cov.: 4 AF XY: 0.0344 AC XY: 8163 AN XY: 237280

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0121 AC: 115 AN: 9520

American (AMR) AF: 0.0136 AC: 189 AN: 13860

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 277 AN: 6128

East Asian (EAS) AF: 0.00950 AC: 66 AN: 6950

South Asian (SAS) AF: 0.0179 AC: 610 AN: 34166

European-Finnish (FIN) AF: 0.0665 AC: 705 AN: 10598

Middle Eastern (MID) AF: 0.0500 AC: 53 AN: 1060

European-Non Finnish (NFE) AF: 0.0368 AC: 13866 AN: 376836

Other (OTH) AF: 0.0397 AC: 717 AN: 18054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00570 AC: 318 AN: 55774 Hom.: 2 Cov.: 0 AF XY: 0.00573 AC XY: 154 AN XY: 26886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00175 AC: 26 AN: 14818

American (AMR) AF: 0.00518 AC: 29 AN: 5596

Ashkenazi Jewish (ASJ) AF: 0.00424 AC: 5 AN: 1180

East Asian (EAS) AF: 0.00234 AC: 3 AN: 1284

South Asian (SAS) AF: 0.00473 AC: 8 AN: 1690

European-Finnish (FIN) AF: 0.00952 AC: 27 AN: 2836

Middle Eastern (MID) AF: 0.0192 AC: 2 AN: 104

European-Non Finnish (NFE) AF: 0.00770 AC: 208 AN: 27028

Other (OTH) AF: 0.00744 AC: 6 AN: 806

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0408 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.75
PhyloP100		-0.073
Mutation Taster		=100/0	polymorphism

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: rs45552041; hg19: chr11-17548704; COSMIC: COSV50014841;