1-216046486-T-C

Position:

• chr1-216046486-T-C

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.6270A>G​(p.Leu2090=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,613,842 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (44 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.162

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=-0.78).
• BP6: Variant 1-216046486-T-C is Benign according to our data. Variant chr1-216046486-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216046486-T-C is described in Lovd as [Benign]. Variant chr1-216046486-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.6270A>G	p.Leu2090=	synonymous_variant	32/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.6270A>G	p.Leu2090=	synonymous_variant	32/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.6270A>G	p.Leu2090=	synonymous_variant	32/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 607 AN: 152134 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00393 AC: 988 AN: 251124 Hom.: 2 AF XY: 0.00396 AC XY: 537 AN XY: 135700

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00554 AC: 8098 AN: 1461590 Hom.: 44 Cov.: 34 AF XY: 0.00536 AC XY: 3899 AN XY: 727098

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.00637

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00399 AC: 607 AN: 152252 Hom.: 3 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74438

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00551

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00505 Hom.: 2

Bravo AF: 0.00317

EpiCase AF: 0.00431

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	USH2A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	Leu2090Leu in exon 32 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction, has been identified in 0.4% (31/7020) of European American ch romosomes and 0.2% (6/3738) African American chromosomes by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; rs56245532), and is reported a s benign in one publication (McGee 2010). -

Usher syndrome type 2A Benign:2

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

Retinitis pigmentosa 39 Benign:1

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	-0.78
CADD	Benign	4.0
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs56245532; hg19: chr1-216219828; COSMIC: COSV56391052;