rs878208

Variant names:

• chr11-17500539-C-T
• rs878208
• NM_153676.4:c.2380+512G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_153676.4(USH1C):​c.2380+512G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,174 control chromosomes in the GnomAD database, including 5,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (5027 hom., cov: 33)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.679
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2380+512G>A		intron_variant	Intron 23 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1480+512G>A		intron_variant	Intron 18 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2380+512G>A		intron_variant	Intron 23 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1480+512G>A		intron_variant	Intron 18 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32079 AN: 152054 Hom.: 5006 Cov.: 33

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.0866

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.211 AC: 32134 AN: 152174 Hom.: 5027 Cov.: 33 AF XY: 0.209 AC XY: 15517 AN XY: 74398

African (AFR) AF: 0.442 AC: 18346 AN: 41474

American (AMR) AF: 0.145 AC: 2215 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3468

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5180

South Asian (SAS) AF: 0.270 AC: 1298 AN: 4816

European-Finnish (FIN) AF: 0.0866 AC: 919 AN: 10616

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8054 AN: 68002

Other (OTH) AF: 0.199 AC: 420 AN: 2114

Alfa AF: 0.144 Hom.: 4088

Bravo AF: 0.222

Asia WGS AF: 0.194 AC: 678 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.9
DANN	Benign	0.54
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878208; hg19: chr11-17522086;