11-17501927-G-A

Variant names:

• chr11-17501927-G-A
• rs17703528
• NM_153676.4:c.2226+12C>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.2226+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 1,612,542 control chromosomes in the GnomAD database, including 4,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (343 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3835 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.423
• Publications: 7 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=-0.83).
• BP6: Variant 11-17501927-G-A is Benign according to our data. Variant chr11-17501927-G-A is described in ClinVar as Benign. ClinVar VariationId is 47995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 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.2226+12C>T		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1326+12C>T		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1512+12C>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.2226+12C>T		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1326+12C>T		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1269+12C>T		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8705 AN: 152030 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0542

GnomAD2 exomes AF: 0.0645 AC: 16163 AN: 250542 AF XY: 0.0711

Gnomad AFR exome AF: 0.0663

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0587

GnomAD4 exome AF: 0.0599 AC: 87410 AN: 1460394 Hom.: 3835 Cov.: 31 AF XY: 0.0636 AC XY: 46170 AN XY: 726474

African (AFR) AF: 0.0633 AC: 2119 AN: 33454

American (AMR) AF: 0.0313 AC: 1396 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.0362 AC: 943 AN: 26052

East Asian (EAS) AF: 0.0362 AC: 1438 AN: 39694

South Asian (SAS) AF: 0.197 AC: 16958 AN: 85984

European-Finnish (FIN) AF: 0.0335 AC: 1788 AN: 53398

Middle Eastern (MID) AF: 0.0759 AC: 437 AN: 5760

European-Non Finnish (NFE) AF: 0.0526 AC: 58466 AN: 1111082

Other (OTH) AF: 0.0641 AC: 3865 AN: 60336

GnomAD4 genome AF: 0.0572 AC: 8701 AN: 152148 Hom.: 343 Cov.: 32 AF XY: 0.0579 AC XY: 4307 AN XY: 74394

African (AFR) AF: 0.0636 AC: 2640 AN: 41502

American (AMR) AF: 0.0422 AC: 646 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.0381 AC: 196 AN: 5150

South Asian (SAS) AF: 0.199 AC: 957 AN: 4816

European-Finnish (FIN) AF: 0.0355 AC: 376 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0530 AC: 3601 AN: 68002

Other (OTH) AF: 0.0551 AC: 116 AN: 2106

Alfa AF: 0.0557 Hom.: 512

Bravo AF: 0.0549

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.47
PhyloP100		-0.42
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs17703528; hg19: chr11-17523474; COSMIC: COSV50046257;