NM_153676.4:c.2457G>C

Variant names:

• chr11-17498195-C-G
• rs1064074
• NM_153676.4:c.2457G>C

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.2457G>C​(p.Glu819Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,664 control chromosomes in the GnomAD database, including 225,739 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E819delinsDAD) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.49 (18621 hom., cov: 32)
  • Exomes 𝑓: 0.53 (207118 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.448
• Publications: 42 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 (MetaRNN=1.8322468E-4).
• BP6: Variant 11-17498195-C-G is Benign according to our data. Variant chr11-17498195-C-G is described in ClinVar as Benign. ClinVar VariationId is 48003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 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.2457G>C	p.Glu819Asp	missense	Exon 24 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1557G>C	p.Glu519Asp	missense	Exon 19 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1743G>C	p.Glu581Asp	missense	Exon 20 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.2457G>C	p.Glu819Asp	missense	Exon 24 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1557G>C	p.Glu519Asp	missense	Exon 19 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1500G>C	p.Glu500Asp	missense	Exon 18 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74212 AN: 151930 Hom.: 18617 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.499

GnomAD2 exomes AF: 0.484 AC: 121669 AN: 251422 AF XY: 0.490

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.308

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.502

GnomAD4 exome AF: 0.529 AC: 772714 AN: 1461614 Hom.: 207118 Cov.: 55 AF XY: 0.527 AC XY: 383308 AN XY: 727112

African (AFR) AF: 0.418 AC: 13992 AN: 33476

American (AMR) AF: 0.368 AC: 16435 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 13497 AN: 26132

East Asian (EAS) AF: 0.305 AC: 12115 AN: 39692

South Asian (SAS) AF: 0.451 AC: 38939 AN: 86244

European-Finnish (FIN) AF: 0.529 AC: 28259 AN: 53408

Middle Eastern (MID) AF: 0.462 AC: 2664 AN: 5766

European-Non Finnish (NFE) AF: 0.554 AC: 616212 AN: 1111792

Other (OTH) AF: 0.507 AC: 30601 AN: 60384

GnomAD4 genome AF: 0.488 AC: 74244 AN: 152050 Hom.: 18621 Cov.: 32 AF XY: 0.485 AC XY: 36041 AN XY: 74320

African (AFR) AF: 0.425 AC: 17596 AN: 41442

American (AMR) AF: 0.408 AC: 6243 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1820 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1542 AN: 5160

South Asian (SAS) AF: 0.443 AC: 2136 AN: 4820

European-Finnish (FIN) AF: 0.537 AC: 5679 AN: 10566

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37540 AN: 67982

Other (OTH) AF: 0.496 AC: 1049 AN: 2114

Alfa AF: 0.518 Hom.: 14963

Bravo AF: 0.477

TwinsUK AF: 0.548 AC: 2033

ALSPAC AF: 0.559 AC: 2156

ESP6500AA AF: 0.429 AC: 1886

ESP6500EA AF: 0.559 AC: 4803

ExAC AF: 0.487 AC: 59176

Asia WGS AF: 0.372 AC: 1297 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.562

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Usher syndrome type 1C (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.45
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.068
Sift	Benign	0.089	T
Sift4G	Uncertain	0.037	D
Polyphen		0.013	B
Vest4		0.17
MutPred		0.35		Loss of ubiquitination at K524 (P = 0.1435)
MPC		0.072
ClinPred		0.012	T
GERP RS		3.4
Varity_R		0.24
gMVP		0.65
Mutation Taster		=89/11	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: rs1064074; hg19: chr11-17519742; COSMIC: COSV50014830; COSMIC: COSV50014830;