chr1-215648567-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.14543G>A(p.Arg4848Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,614,022 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4848W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 22 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 291 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.55

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008491486).

BP6

Variant 1-215648567-C-T is Benign according to our data. Variant chr1-215648567-C-T is described in ClinVar as Benign. ClinVar VariationId is 48444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.14543G>A	p.Arg4848Gln	missense_variant	Exon 66 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.14543G>A	p.Arg4848Gln	missense_variant	Exon 66 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.14543G>A	p.Arg4848Gln	missense_variant	Exon 66 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00588

AC:

895

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0294

Gnomad SAS

AF:

0.0631

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00350

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.0115

AC:

2894

AN:

251102

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0189

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00377

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00868

AC:

12684

AN:

1461758

Hom.:

291

Cov.:

AF XY:

0.0101

AC XY:

7378

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.00206

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.0506

AC:

2009

AN:

39700

South Asian (SAS)

AF:

0.0597

AC:

5145

AN:

86220

European-Finnish (FIN)

AF:

0.00253

AC:

135

AN:

53420

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00426

AC:

4742

AN:

1111916

Other (OTH)

AF:

0.00833

AC:

503

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

689

1378

2068

2757

3446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00588

AC:

896

AN:

152264

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

529

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41570

American (AMR)

AF:

0.00602

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0294

AC:

152

AN:

5162

South Asian (SAS)

AF:

0.0633

AC:

305

AN:

4816

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00350

AC:

238

AN:

68020

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.00431

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.0122

AC:

1486

Asia WGS

AF:

0.0410

AC:

143

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 19, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

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

- -

Jan 16, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.019

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

PhyloP100

1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

1.1

REVEL

Benign

0.072

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.038

MPC

0.032

ClinPred

0.0014

GERP RS

2.0

Varity_R

0.016

gMVP

0.15

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over