rs115155428

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001106.4(ACVR2B):c.1075-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,613,656 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 5 hom., cov: 29)

Exomes 𝑓: 0.0084 ( 64 hom. )

Consequence

ACVR2B
NM_001106.4 splice_region, intron

Scores

Splicing: ADA: 0.00002324

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.771

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 3-38482193-C-T is Benign according to our data. Variant chr3-38482193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 976 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4 link	c.1075-5C>T		splice_region_variant, intron_variant	Intron 8 of 10	ENST00000352511.5	NP_001097.2	Q13705-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR2B	ENST00000352511.5 link	c.1075-5C>T	splice_region_variant, intron_variant	Intron 8 of 10	1	NM_001106.4	ENSP00000340361.3	Q13705-1
ACVR2B	ENST00000461232.1 link	n.4864-5C>T	splice_region_variant, intron_variant	Intron 7 of 9	1
ACVR2B	ENST00000465020.5 link	n.1161-5C>T	splice_region_variant, intron_variant	Intron 7 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

976

AN:

151678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00187

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00840

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00133

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00670

AC:

1685

AN:

251410

AF XY:

0.00668

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.00840

AC:

12284

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00842

AC XY:

6121

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

33480

American (AMR)

AF:

0.00809

AC:

362

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00784

AC:

205

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00143

AC:

123

AN:

86256

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00980

AC:

10895

AN:

1111994

Other (OTH)

AF:

0.00782

AC:

472

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

727

1454

2181

2908

3635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00643

AC:

976

AN:

151796

Hom.:

Cov.:

AF XY:

0.00603

AC XY:

447

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

41342

American (AMR)

AF:

0.00839

AC:

128

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00105

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0103

AC:

698

AN:

67936

Other (OTH)

AF:

0.0114

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

142

189

236

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:

0.00799

Hom.:

Bravo

AF:

0.00685

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal

Benign:4

Jan 13, 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. -

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

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Sep 24, 2013

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACVR2B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.28

(source)

DANN

Benign

0.69

PhyloP100

-0.77

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

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