chr11-17521006-C-T

Variant names:

• chr11-17521006-C-T
• rs11024318
• NM_153676.4:c.1086-12G>A

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.1086-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,613,244 control chromosomes in the GnomAD database, including 3,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (909 hom., cov: 31)
  • Exomes 𝑓: 0.046 (2180 hom.)
• Consequence: USH1C NM_153676.4 intron
• Scores: Splicing: ADA: 0.00004067
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.118
• Publications: 10 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=-0.59).
• BP6: Variant 11-17521006-C-T is Benign according to our data. Variant chr11-17521006-C-T is described in ClinVar as Benign. ClinVar VariationId is 47974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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.1086-12G>A		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1086-12G>A		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1119-12G>A		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.1086-12G>A		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1086-12G>A		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1029-12G>A		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0861 AC: 13084 AN: 152014 Hom.: 897 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0208

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0852

GnomAD2 exomes AF: 0.0603 AC: 15159 AN: 251444 AF XY: 0.0550

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0313

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0465 AC: 67897 AN: 1461112 Hom.: 2180 Cov.: 47 AF XY: 0.0454 AC XY: 33004 AN XY: 726884

African (AFR) AF: 0.196 AC: 6564 AN: 33432

American (AMR) AF: 0.101 AC: 4534 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0869 AC: 2270 AN: 26132

East Asian (EAS) AF: 0.0364 AC: 1445 AN: 39694

South Asian (SAS) AF: 0.0277 AC: 2393 AN: 86252

European-Finnish (FIN) AF: 0.0404 AC: 2153 AN: 53350

Middle Eastern (MID) AF: 0.0807 AC: 465 AN: 5764

European-Non Finnish (NFE) AF: 0.0402 AC: 44651 AN: 1111392

Other (OTH) AF: 0.0567 AC: 3422 AN: 60376

GnomAD4 genome AF: 0.0864 AC: 13138 AN: 152132 Hom.: 909 Cov.: 31 AF XY: 0.0843 AC XY: 6271 AN XY: 74392

African (AFR) AF: 0.191 AC: 7910 AN: 41452

American (AMR) AF: 0.0881 AC: 1346 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0859 AC: 298 AN: 3470

East Asian (EAS) AF: 0.0316 AC: 164 AN: 5182

South Asian (SAS) AF: 0.0206 AC: 99 AN: 4814

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10608

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2733 AN: 68006

Other (OTH) AF: 0.0844 AC: 178 AN: 2110

Alfa AF: 0.0562 Hom.: 201

Bravo AF: 0.0964

Asia WGS AF: 0.0420 AC: 144 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (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	-0.59
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		0.12
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.020		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: rs11024318; hg19: chr11-17542553; COSMIC: COSV107202986; COSMIC: COSV107202986;