rs2070489

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001106.4(ACVR2B):c.333A>G(p.Glu111Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,688 control chromosomes in the GnomAD database, including 283,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21882 hom., cov: 31)

Exomes 𝑓: 0.60 ( 262023 hom. )

Consequence

ACVR2B
NM_001106.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.44

Publications

24 publications found

Variant links:

Genes affected

ACVR2B (HGNC:174): (activin A receptor type 2B) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Type II receptors are considered to be constitutively active kinases. This gene encodes activin A type IIB receptor, which displays a 3- to 4-fold higher affinity for the ligand than activin A type II receptor. [provided by RefSeq, Jul 2008]

ACVR2B Gene-Disease associations (from GenCC):

heterotaxy, visceral, 4, autosomal
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACVR2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 3-38477933-A-G is Benign according to our data. Variant chr3-38477933-A-G is described in ClinVar as Benign. ClinVar VariationId is 257468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4 link	c.333A>G	p.Glu111Glu	synonymous_variant	Exon 3 of 11	ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ACVR2B	ENST00000352511.5 link	c.333A>G	p.Glu111Glu	synonymous_variant	Exon 3 of 11	1	NM_001106.4	ENSP00000340361.3
ACVR2B	ENST00000461232.1 link	n.4122A>G		non_coding_transcript_exon_variant	Exon 2 of 10	1
ACVR2B	ENST00000465020.5 link	n.337A>G		non_coding_transcript_exon_variant	Exon 3 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79342

AN:

151826

Hom.:

21878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.563

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.573

Gnomad FIN

AF:

0.555

Gnomad MID

AF:

0.510

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.533

GnomAD2 exomes

AF:

0.565

AC:

141862

AN:

251146

AF XY:

0.572

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.533

Gnomad ASJ exome

AF:

0.557

Gnomad EAS exome

AF:

0.469

Gnomad FIN exome

AF:

0.559

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.575

GnomAD4 exome

AF:

0.596

AC:

870869

AN:

1461744

Hom.:

262023

Cov.:

AF XY:

0.596

AC XY:

433725

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.333

AC:

11160

AN:

33478

American (AMR)

AF:

0.534

AC:

23869

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14475

AN:

26128

East Asian (EAS)

AF:

0.467

AC:

18529

AN:

39696

South Asian (SAS)

AF:

0.581

AC:

50095

AN:

86256

European-Finnish (FIN)

AF:

0.567

AC:

30253

AN:

53376

Middle Eastern (MID)

AF:

0.508

AC:

2929

AN:

5764

European-Non Finnish (NFE)

AF:

0.616

AC:

685067

AN:

1111934

Other (OTH)

AF:

0.571

AC:

34492

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

21066

42132

63197

84263

105329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18268

36536

54804

73072

91340

<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:

0.522

AC:

79382

AN:

151944

Hom.:

21882

Cov.:

AF XY:

0.520

AC XY:

38626

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.346

AC:

14333

AN:

41432

American (AMR)

AF:

0.542

AC:

8285

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

1951

AN:

3468

East Asian (EAS)

AF:

0.462

AC:

2378

AN:

5144

South Asian (SAS)

AF:

0.573

AC:

2757

AN:

4810

European-Finnish (FIN)

AF:

0.555

AC:

5861

AN:

10560

Middle Eastern (MID)

AF:

0.507

AC:

148

AN:

292

European-Non Finnish (NFE)

AF:

0.620

AC:

42107

AN:

67946

Other (OTH)

AF:

0.532

AC:

1121

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1829

3658

5488

7317

9146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.577

Hom.:

78292

Bravo

AF:

0.510

Asia WGS

AF:

0.522

AC:

1814

AN:

3478

EpiCase

AF:

0.603

EpiControl

AF:

0.607

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal

Benign:5

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.8

(source)

DANN

Benign

0.63

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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