rs377002861

Variant names:

• chr11-17509480-A-G
• rs377002861
• NM_153676.4:c.1889T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-17509480-A-G
• chr11-17509480-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000005226.12(USH1C):​c.1889T>C​(p.Leu630Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00003 in 1,466,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: USH1C ENST00000005226.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78
• Publications: 0 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 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000005226.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.1889T>C	p.Leu630Pro	missense	Exon 18 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7500T>C		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1470+2422T>C		intron	N/A	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1889T>C	p.Leu630Pro	missense	Exon 18 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7500T>C		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1228-7500T>C		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.000137 AC: 18 AN: 131562 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251054 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 26 AN: 1335248 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 9 AN XY: 661898

African (AFR) AF: 0.000704 AC: 21 AN: 29832

American (AMR) AF: 0.0000245 AC: 1 AN: 40758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21484

East Asian (EAS) AF: 0.00 AC: 0 AN: 29264

South Asian (SAS) AF: 0.00 AC: 0 AN: 85024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 9.71e-7 AC: 1 AN: 1029482

Other (OTH) AF: 0.0000577 AC: 3 AN: 52020

GnomAD4 genome AF: 0.000137 AC: 18 AN: 131562 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 8 AN XY: 62392

African (AFR) AF: 0.000512 AC: 18 AN: 35150

American (AMR) AF: 0.00 AC: 0 AN: 11594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 3880

South Asian (SAS) AF: 0.00 AC: 0 AN: 3778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64142

Other (OTH) AF: 0.00 AC: 0 AN: 1834

Alfa AF: 0.000161 Hom.: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	-0.030
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.35	T
Vest4		0.69
MVP		0.45
MPC		0.13
ClinPred		0.70	D
GERP RS		5.9
gMVP		0.38
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377002861; hg19: chr11-17531027;