rs2070489

Positions:

• chr3-38477933-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001106.4(ACVR2B):​c.333A>G​(p.Glu111=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.44

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 257468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38477933-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ACVR2B	NM_001106.4	c.333A>G	p.Glu111=	synonymous_variant	3/11	ENST00000352511.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2B	ENST00000352511.5	c.333A>G	p.Glu111=	synonymous_variant	3/11	1	NM_001106.4	P1
ACVR2B	ENST00000461232.1	n.4122A>G		non_coding_transcript_exon_variant	2/10	1
ACVR2B	ENST00000465020.5	n.337A>G		non_coding_transcript_exon_variant	3/10	2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79342 AN: 151826 Hom.: 21878 Cov.: 31

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

GnomAD3 exomes AF: 0.565 AC: 141862 AN: 251146 Hom.: 40827 AF XY: 0.572 AC XY: 77660 AN XY: 135840

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 SAS exome AF: 0.579

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.: 66 AF XY: 0.596 AC XY: 433725 AN XY: 727186

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.554

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.581

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.571

GnomAD4 genome AF: 0.522 AC: 79382 AN: 151944 Hom.: 21882 Cov.: 31 AF XY: 0.520 AC XY: 38626 AN XY: 74242

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.555

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.532

Alfa AF: 0.591 Hom.: 51533

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.8
DANN	Benign	0.63

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

Other links and lift over

dbSNP: rs2070489; hg19: chr3-38519424; COSMIC: COSV61702341;