rs3749386

Positions:

• chr3-38454574-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001106.4(ACVR2B):​c.52+200C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 398,990 control chromosomes in the GnomAD database, including 47,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14853 hom., cov: 33)
  • Exomes 𝑓: 0.51 (33095 hom.)
• Consequence: ACVR2B NM_001106.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.128

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-38454574-C-T is Benign according to our data. Variant chr3-38454574-C-T is described in ClinVar as [Benign]. Clinvar id is 1183589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38454574-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.52+200C>T		intron_variant		ENST00000352511.5	NP_001097.2
ACVR2B	XM_017007515.3	c.-41C>T		5_prime_UTR_variant	1/11		XP_016863004.1
ACVR2B-AS1	NR_028389.1	n.247G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.52+200C>T		intron_variant		1	NM_001106.4	ENSP00000340361.3
ACVR2B-AS1	ENST00000441531.1	n.247G>A		non_coding_transcript_exon_variant	1/2	2
ACVR2B	ENST00000465020.5	n.56+200C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59857 AN: 151992 Hom.: 14858 Cov.: 33

Gnomad AFR AF: 0.0973

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.508 AC: 125301 AN: 246884 Hom.: 33095 Cov.: 4 AF XY: 0.511 AC XY: 63933 AN XY: 125228

Gnomad4 AFR exome AF: 0.0943

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.457

GnomAD4 genome AF: 0.393 AC: 59842 AN: 152106 Hom.: 14853 Cov.: 33 AF XY: 0.392 AC XY: 29179 AN XY: 74352

Gnomad4 AFR AF: 0.0969

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.556

Gnomad4 OTH AF: 0.414

Alfa AF: 0.476 Hom.: 6402

Bravo AF: 0.363

Asia WGS AF: 0.389 AC: 1351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.7
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs3749386; hg19: chr3-38496065;