rs55921307

chr1-215680350-G-Achr1-215680350-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_206933.4(USH2A):c.12093C>T(p.Tyr4031=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,796 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0790

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-215680350-G-A is Benign according to our data. Variant chr1-215680350-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215680350-G-A is described in Lovd as [Benign]. Variant chr1-215680350-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.079 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.12093C>T	p.Tyr4031=	synonymous_variant	62/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.12093C>T	p.Tyr4031=	synonymous_variant	62/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.12093C>T	p.Tyr4031=	synonymous_variant	62/73

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 151872 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00421

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00304 AC: 761 AN: 250532 Hom.: 3 AF XY: 0.00307 AC XY: 416 AN XY: 135378

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00341 AC: 4992 AN: 1461822 Hom.: 16 Cov.: 32 AF XY: 0.00339 AC XY: 2465 AN XY: 727214

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.00396

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00290 AC: 440 AN: 151974 Hom.: 1 Cov.: 32 AF XY: 0.00295 AC XY: 219 AN XY: 74272

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00143

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00315

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2012	Tyr4031Tyr in exon 62 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.46% (32/7020) of Europ ean American chromosomes and 0.08% (3/3738) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs55921307) and has been reported in cases (5/651 (0.7%)) and controls (9/4482 (0.2%)) with statistically insignificant differences in frequen cy (Dreyer 2008, McGee 2010, Yan 2009). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	USH2A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.12
Dann	Benign	0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55921307; hg19: chr1-215853692; COSMIC: COSV56349142;