rs138547759

Variant names:

• chr11-17504635-G-A
• rs138547759
• NM_153676.4:c.2184+12C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17504635-G-A
• chr11-17504635-G-C
• chr11-17504635-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_153676.4(USH1C):​c.2184+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,613,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17504635-G-A is Benign according to our data. Variant chr11-17504635-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17504635-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152176) while in subpopulation AFR AF= 0.00489 (203/41506). AF 95% confidence interval is 0.00434. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2184+12C>T		intron_variant	Intron 20 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-2655C>T		intron_variant	Intron 15 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2184+12C>T		intron_variant	Intron 20 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1285-2655C>T		intron_variant	Intron 15 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152058 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000449 AC: 113 AN: 251460 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135904

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727188

Gnomad4 AFR exome AF: 0.00556

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152176 Hom.: 1 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74408

Gnomad4 AFR AF: 0.00489

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000428 Hom.: 0

Bravo AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

2184+12C>T in Intron 20 of USH1C: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 0.5% (20/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs138547759). -

not provided Benign:1

May 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs138547759; hg19: chr11-17526182;