rs150752796

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001106.4(ACVR2B):c.1477C>T(p.Leu493Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000525 in 1,613,968 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

ACVR2B
NM_001106.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.58

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18834609).

BP6

Variant 3-38483270-C-T is Benign according to our data. Variant chr3-38483270-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 344920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4 link	c.1477C>T	p.Leu493Phe	missense_variant	Exon 11 of 11	ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ACVR2B	ENST00000352511.5 link	c.1477C>T	p.Leu493Phe	missense_variant	Exon 11 of 11	1	NM_001106.4	ENSP00000340361.3
ACVR2B	ENST00000461232.1 link	n.5266C>T		non_coding_transcript_exon_variant	Exon 10 of 10	1
ACVR2B	ENST00000465020.5 link	n.1563C>T		non_coding_transcript_exon_variant	Exon 10 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

251494

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000439

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000553

AC:

809

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000656

AC:

730

AN:

1112006

Other (OTH)

AF:

0.00118

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000256

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000442

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACVR2B: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.039

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

1.7

PhyloP100

4.6

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.74

REVEL

Uncertain

0.34

Sift

Benign

0.061

Sift4G

Benign

0.21

Polyphen

0.73

Vest4

0.25

MVP

0.67

MPC

1.2

ClinPred

0.033

GERP RS

5.2

Varity_R

0.16

gMVP

0.54

Mutation Taster

=69/31

polymorphism

(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