Genetic Variant USH2A:p.Thr4204Thr (chr1-215675299-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_206933.4(USH2A):c.12612A>G(p.Thr4204Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 1,613,914 control chromosomes in the GnomAD database, including 503,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43060 hom., cov: 33)

Exomes 𝑓: 0.79 ( 460076 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.101

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-215675299-T-C is Benign according to our data. Variant chr1-215675299-T-C is described in ClinVar as [Benign]. Clinvar id is 177993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.101 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12612A>G	p.Thr4204Thr	synonymous_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.12612A>G	p.Thr4204Thr	synonymous_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.12612A>G	p.Thr4204Thr	synonymous_variant	Exon 63 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.748

AC:

113712

AN:

152030

Hom.:

43036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.635

Gnomad AMI

AF:

0.919

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.785

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.744

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.813

Gnomad OTH

AF:

0.786

GnomAD3 exomes

AF:

0.767

AC:

191133

AN:

249244

Hom.:

73901

AF XY:

0.767

AC XY:

103433

AN XY:

134862

show subpopulations

Gnomad AFR exome

AF:

0.629

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.797

Gnomad EAS exome

AF:

0.647

Gnomad SAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.748

Gnomad NFE exome

AF:

0.812

Gnomad OTH exome

AF:

0.794

GnomAD4 exome

AF:

0.792

AC:

1157157

AN:

1461764

Hom.:

460076

Cov.:

AF XY:

0.789

AC XY:

574029

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.628

Gnomad4 AMR exome

AF:

0.808

Gnomad4 ASJ exome

AF:

0.788

Gnomad4 EAS exome

AF:

0.627

Gnomad4 SAS exome

AF:

0.701

Gnomad4 FIN exome

AF:

0.752

Gnomad4 NFE exome

AF:

0.812

Gnomad4 OTH exome

AF:

0.777

GnomAD4 genome

AF:

0.748

AC:

113790

AN:

152150

Hom.:

43060

Cov.:

AF XY:

0.744

AC XY:

55328

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.635

Gnomad4 AMR

AF:

0.799

Gnomad4 ASJ

AF:

0.785

Gnomad4 EAS

AF:

0.645

Gnomad4 SAS

AF:

0.680

Gnomad4 FIN

AF:

0.744

Gnomad4 NFE

AF:

0.813

Gnomad4 OTH

AF:

0.787

Alfa

AF:

0.798

Hom.:

85033

Bravo

AF:

0.747

Asia WGS

AF:

0.654

AC:

2274

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inferred frequency = 273/386 (LMM data) -

Aug 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Usher syndrome type 2A

Benign:2

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39

Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.36

DANN

Benign

0.36

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