rs1046048

Positions:

• chr3-38483251-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001106.4(ACVR2B):​c.1458C>T​(p.Asn486=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,586 control chromosomes in the GnomAD database, including 232,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16163 hom., cov: 30)
  • Exomes 𝑓: 0.54 (215859 hom.)
• Consequence: ACVR2B NM_001106.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.06

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 3-38483251-C-T is Benign according to our data. Variant chr3-38483251-C-T is described in ClinVar as [Benign]. Clinvar id is 257467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38483251-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.1458C>T	p.Asn486=	synonymous_variant	11/11	ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.1458C>T	p.Asn486=	synonymous_variant	11/11	1	NM_001106.4	ENSP00000340361	P1
ACVR2B	ENST00000461232.1	n.5247C>T		non_coding_transcript_exon_variant	10/10	1
ACVR2B	ENST00000465020.5	n.1544C>T		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64752 AN: 151688 Hom.: 16164 Cov.: 30

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.447

GnomAD3 exomes AF: 0.477 AC: 119999 AN: 251464 Hom.: 30882 AF XY: 0.491 AC XY: 66754 AN XY: 135906

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.269

Gnomad SAS exome AF: 0.520

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.536 AC: 783446 AN: 1461780 Hom.: 215859 Cov.: 60 AF XY: 0.537 AC XY: 390623 AN XY: 727204

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.427 AC: 64754 AN: 151806 Hom.: 16163 Cov.: 30 AF XY: 0.424 AC XY: 31420 AN XY: 74146

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.510

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.447

Alfa AF: 0.522 Hom.: 27658

Bravo AF: 0.400

Asia WGS AF: 0.401 AC: 1392 AN: 3478

EpiCase AF: 0.554

EpiControl AF: 0.562

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:5

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

not specified Benign:4

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+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.35
CADD	Benign	9.1
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1046048; hg19: chr3-38524742; COSMIC: COSV61701004;