11-17509510-C-G

Variant names:

• chr11-17509510-C-G
• rs139996942
• NM_153676.4:c.1859G>C

Variant summary

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

The NM_153676.4(USH1C):​c.1859G>C​(p.Arg620Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R620C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• 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 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: NM_153676.4. 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.1859G>C	p.Arg620Pro	missense	Exon 18 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7530G>C		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1470+2392G>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.1859G>C	p.Arg620Pro	missense	Exon 18 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7530G>C		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1228-7530G>C		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 35214 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000256 AC: 14 AN: 546476 Hom.: 0 Cov.: 34 AF XY: 0.0000322 AC XY: 9 AN XY: 279120

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16634

American (AMR) AF: 0.00 AC: 0 AN: 30084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10908

East Asian (EAS) AF: 0.00 AC: 0 AN: 10764

South Asian (SAS) AF: 0.00 AC: 0 AN: 46196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2974

European-Non Finnish (NFE) AF: 0.0000366 AC: 14 AN: 383012

Other (OTH) AF: 0.00 AC: 0 AN: 20742

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 35256 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16822

African (AFR) AF: 0.00 AC: 0 AN: 10444

American (AMR) AF: 0.00 AC: 0 AN: 2504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 918

East Asian (EAS) AF: 0.00 AC: 0 AN: 1586

South Asian (SAS) AF: 0.00 AC: 0 AN: 1034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 16976

Other (OTH) AF: 0.00 AC: 0 AN: 424

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.88	T
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Benign	1.0	T
Vest4		0.53
MutPred		0.34		Gain of glycosylation at T617 (P = 0.0148)
MVP		0.57
MPC		0.088
ClinPred		0.96	D
GERP RS		5.9
gMVP		0.24
Mutation Taster		=70/30	polymorphism

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: rs139996942; hg19: chr11-17531057; COSMIC: COSV104991158; COSMIC: COSV104991158;