rs12095085

Positions:

• chr1-215758586-T-A
• chr1-215758586-T-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.11389+9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,609,608 control chromosomes in the GnomAD database, including 13,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1273 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11837 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.449

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-215758586-T-A is Benign according to our data. Variant chr1-215758586-T-A is described in ClinVar as [Benign]. Clinvar id is 48372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215758586-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.11389+9A>T		intron_variant		ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.11389+9A>T		intron_variant		1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.11389+9A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18727 AN: 151992 Hom.: 1271 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0990

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.104 AC: 26024 AN: 250720 Hom.: 1682 AF XY: 0.104 AC XY: 14106 AN XY: 135566

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0683

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0526

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.123 AC: 179171 AN: 1457498 Hom.: 11837 Cov.: 34 AF XY: 0.122 AC XY: 88177 AN XY: 725324

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0699

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0545

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.123 AC: 18731 AN: 152110 Hom.: 1273 Cov.: 32 AF XY: 0.122 AC XY: 9048 AN XY: 74344

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0987

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0450

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.142

Alfa AF: 0.104 Hom.: 334

Bravo AF: 0.120

Asia WGS AF: 0.0250 AC: 88 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.55

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: rs12095085; hg19: chr1-215931928;