rs12404427

Positions:

• chr1-215900163-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.7506G>A​(p.Pro2502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,613,400 control chromosomes in the GnomAD database, including 6,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (470 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5609 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.03

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-215900163-C-T is Benign according to our data. Variant chr1-215900163-C-T is described in ClinVar as [Benign]. Clinvar id is 48584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215900163-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7506G>A	p.Pro2502=	synonymous_variant	40/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7506G>A	p.Pro2502=	synonymous_variant	40/72	1	NM_206933.4	ENSP00000305941	P1
	ENST00000414995.1	n.61-562C>T		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7506G>A	p.Pro2502=	synonymous_variant	40/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11471 AN: 151954 Hom.: 470 Cov.: 33

Gnomad AFR AF: 0.0816

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0684 AC: 17142 AN: 250672 Hom.: 694 AF XY: 0.0676 AC XY: 9154 AN XY: 135452

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0567

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0782

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0835 AC: 121987 AN: 1461328 Hom.: 5609 Cov.: 32 AF XY: 0.0823 AC XY: 59840 AN XY: 726974

Gnomad4 AFR exome AF: 0.0809

Gnomad4 AMR exome AF: 0.0916

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.0582

Gnomad4 FIN exome AF: 0.0521

Gnomad4 NFE exome AF: 0.0915

Gnomad4 OTH exome AF: 0.0740

GnomAD4 genome AF: 0.0755 AC: 11478 AN: 152072 Hom.: 470 Cov.: 33 AF XY: 0.0736 AC XY: 5473 AN XY: 74334

Gnomad4 AFR AF: 0.0816

Gnomad4 AMR AF: 0.0843

Gnomad4 ASJ AF: 0.0406

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0537

Gnomad4 FIN AF: 0.0502

Gnomad4 NFE AF: 0.0835

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0769 Hom.: 628

Bravo AF: 0.0760

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0751

EpiControl AF: 0.0759

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2013	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	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -

not provided Benign:2

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.81

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: rs12404427; hg19: chr1-216073505; COSMIC: COSV56327776;