rs149510892

Variant names:

• chr11-17509463-G-A
• rs149510892
• NM_153676.4:c.1906C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17509463-G-A
• chr11-17509463-G-C
• chr11-17509463-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_153676.4(USH1C):​c.1906C>T​(p.Arg636Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R636L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.08
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054422915).
• BP6: Variant 11-17509463-G-A is Benign according to our data. Variant chr11-17509463-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47986.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00124 (189/151918) while in subpopulation AFR AF = 0.00396 (164/41404). AF 95% confidence interval is 0.00347. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1906C>T	p.Arg636Cys	missense	Exon 18 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7483C>T		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1470+2439C>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.1906C>T	p.Arg636Cys	missense	Exon 18 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7483C>T		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1228-7483C>T		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 151800 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000331 AC: 83 AN: 251054 AF XY: 0.000243

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000251 AC: 367 AN: 1461422 Hom.: 0 Cov.: 32 AF XY: 0.000227 AC XY: 165 AN XY: 726952

African (AFR) AF: 0.00335 AC: 112 AN: 33470

American (AMR) AF: 0.000268 AC: 12 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000175 AC: 194 AN: 1111736

Other (OTH) AF: 0.000414 AC: 25 AN: 60368

GnomAD4 genome AF: 0.00124 AC: 189 AN: 151918 Hom.: 0 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74244

African (AFR) AF: 0.00396 AC: 164 AN: 41404

American (AMR) AF: 0.00105 AC: 16 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67958

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000565 Hom.: 0

Bravo AF: 0.00145

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.062	T
Sift4G	Benign	0.12	T
Vest4		0.30
MVP		0.37
MPC		0.082
ClinPred		0.019	T
GERP RS		4.0
gMVP		0.28
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs149510892; hg19: chr11-17531010; COSMIC: COSV50014398; COSMIC: COSV50014398;