rs56829872

Positions:

• chr1-215879003-G-A

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.8319C>T​(p.Ser2773=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,613,946 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.720

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=-0.77).
• BP6: Variant 1-215879003-G-A is Benign according to our data. Variant chr1-215879003-G-A is described in ClinVar as [Benign]. Clinvar id is 178646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215879003-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.72 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.8319C>T	p.Ser2773=	synonymous_variant	42/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.8319C>T	p.Ser2773=	synonymous_variant	42/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.8319C>T	p.Ser2773=	synonymous_variant	42/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00105 AC: 263 AN: 250048 Hom.: 3 AF XY: 0.000754 AC XY: 102 AN XY: 135238

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1461748 Hom.: 5 Cov.: 32 AF XY: 0.000278 AC XY: 202 AN XY: 727184

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74408

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00220 Hom.: 2

Bravo AF: 0.00449

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Ser2773Ser in Exon 42 of USH2A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.4% (54/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs56829872). -

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	-0.77
CADD	Benign	3.2
DANN	Benign	0.62

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: rs56829872; hg19: chr1-216052345; COSMIC: COSV56352469;