1-215728360-C-T

Position:

• chr1-215728360-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.11736G>A​(p.Glu3912Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,614,108 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (386 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (347 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0410

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-215728360-C-T is Benign according to our data. Variant chr1-215728360-C-T is described in ClinVar as [Benign]. Clinvar id is 48381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215728360-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.041 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.11736G>A	p.Glu3912Glu	synonymous_variant	61/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.11736G>A	p.Glu3912Glu	synonymous_variant	61/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.11736G>A	p.Glu3912Glu	synonymous_variant	61/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6173 AN: 152160 Hom.: 387 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0122 AC: 3029 AN: 248804 Hom.: 166 AF XY: 0.00929 AC XY: 1251 AN XY: 134716

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00917

GnomAD4 exome AF: 0.00503 AC: 7353 AN: 1461830 Hom.: 347 Cov.: 33 AF XY: 0.00448 AC XY: 3259 AN XY: 727212

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000795

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0406 AC: 6176 AN: 152278 Hom.: 386 Cov.: 32 AF XY: 0.0385 AC XY: 2866 AN XY: 74462

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0187 Hom.: 80

Bravo AF: 0.0470

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2011	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2009	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
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	- -

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	-0.56
CADD	Benign	5.0
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs56053654; hg19: chr1-215901702;