rs76769358

Variant names:

• chr11-17504709-A-G
• rs76769358
• NM_153676.4:c.2134-12T>C

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.2134-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,541,542 control chromosomes in the GnomAD database, including 2,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (233 hom., cov: 33)
  • Exomes 𝑓: 0.067 (2553 hom.)
• Consequence: USH1C NM_153676.4 intron
• Scores: Splicing: ADA: 0.0002548
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.638
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17504709-A-G is Benign according to our data. Variant chr11-17504709-A-G is described in ClinVar as Benign. ClinVar VariationId is 47989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0696 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.2134-12T>C		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-2729T>C		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1471-2729T>C		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.2134-12T>C		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-2729T>C		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1228-2729T>C		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7454 AN: 150088 Hom.: 234 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0634

GnomAD2 exomes AF: 0.133 AC: 13967 AN: 104990 AF XY: 0.141

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.0665 AC: 92585 AN: 1391358 Hom.: 2553 Cov.: 36 AF XY: 0.0671 AC XY: 46470 AN XY: 692852

African (AFR) AF: 0.0112 AC: 357 AN: 31830

American (AMR) AF: 0.0423 AC: 1818 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2638 AN: 25160

East Asian (EAS) AF: 0.000185 AC: 7 AN: 37776

South Asian (SAS) AF: 0.0567 AC: 4715 AN: 83140

European-Finnish (FIN) AF: 0.0484 AC: 2451 AN: 50678

Middle Eastern (MID) AF: 0.102 AC: 572 AN: 5602

European-Non Finnish (NFE) AF: 0.0722 AC: 76256 AN: 1056618

Other (OTH) AF: 0.0655 AC: 3771 AN: 57614

GnomAD4 genome AF: 0.0496 AC: 7451 AN: 150184 Hom.: 233 Cov.: 33 AF XY: 0.0482 AC XY: 3536 AN XY: 73338

African (AFR) AF: 0.0134 AC: 549 AN: 41082

American (AMR) AF: 0.0556 AC: 838 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 357 AN: 3440

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.0548 AC: 261 AN: 4762

European-Finnish (FIN) AF: 0.0430 AC: 439 AN: 10198

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0713 AC: 4793 AN: 67200

Other (OTH) AF: 0.0629 AC: 131 AN: 2084

Alfa AF: 0.0564 Hom.: 33

Bravo AF: 0.0473

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.74
DANN	Benign	0.54
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0
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: rs76769358; hg19: chr11-17526256; COSMIC: COSV50030144; COSMIC: COSV50030144;