rs646094

Positions:

• chr1-216198592-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.3812-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,608,604 control chromosomes in the GnomAD database, including 41,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3260 hom., cov: 32)
  • Exomes 𝑓: 0.23 (37962 hom.)
• Consequence: USH2A NM_206933.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002956
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.63

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-216198592-A-C is Benign according to our data. Variant chr1-216198592-A-C is described in ClinVar as [Benign]. Clinvar id is 48508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216198592-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.3812-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+2667A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.3812-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.3812-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
USH2A-AS1	ENST00000420867.1	n.362+2667A>C		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.3812-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31090 AN: 151976 Hom.: 3257 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.213 AC: 52476 AN: 246022 Hom.: 5684 AF XY: 0.217 AC XY: 28907 AN XY: 133382

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.230

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.226 AC: 329796 AN: 1456510 Hom.: 37962 Cov.: 32 AF XY: 0.228 AC XY: 165060 AN XY: 724752

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.204 AC: 31103 AN: 152094 Hom.: 3260 Cov.: 32 AF XY: 0.201 AC XY: 14917 AN XY: 74334

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.208

Alfa AF: 0.223 Hom.: 1542

Bravo AF: 0.204

Asia WGS AF: 0.185 AC: 643 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.4
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs646094; hg19: chr1-216371934;