1-215647649-C-T

Position:

chr1-215647649-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_206933.4(USH2A):c.14664G>A(p.Thr4888=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T4888T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -1.41

Variant links:

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 1-215647649-C-T is Benign according to our data. Variant chr1-215647649-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48445.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=1}. Variant chr1-215647649-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.41 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14664G>A	p.Thr4888=	synonymous_variant	67/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.14664G>A	p.Thr4888=	synonymous_variant	67/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14664G>A	p.Thr4888=	synonymous_variant	67/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000692

AC:

174

AN:

251304

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00105

AC:

1531

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

739

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000743

AC:

113

AN:

152158

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000905

Hom.:

Bravo

AF:

0.000812

EpiCase

AF:

0.000818

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 08, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2014

p.Thr4888Thr in exon 67 of USH2A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has been identified in 0.1% (73/67624) of European ch romosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; d bSNP rs111033525). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.25

DANN

Benign

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over