rs2070489

Variant names:

• chr3-38477933-A-G
• rs2070489
• NM_001106.4:c.333A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.44
• Publications: 24 publications found

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	NM_001106.4	MANE Select	c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 11	NP_001097.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	ENST00000352511.5	TSL:1 MANE Select	c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 11	ENSP00000340361.3
	ACVR2B	ENST00000461232.1	TSL:1	n.4122A>G		non_coding_transcript_exon	Exon 2 of 10
	ACVR2B	ENST00000922132.1		c.333A>G	p.Glu111Glu	synonymous	Exon 3 of 11	ENSP00000592191.1

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

GnomAD2 exomes AF: 0.565 AC: 141862 AN: 251146 AF XY: 0.572

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

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

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

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Heterotaxy, visceral, 4, autosomal (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.8
DANN	Benign	0.63
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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