rs3749386

Variant names:

• chr3-38454574-C-T
• rs3749386
• NM_001106.4:c.52+200C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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-AS1 (HGNC:44161): (ACVR2B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1183589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.52+200C>T		intron_variant	Intron 1 of 10	ENST00000352511.5	NP_001097.2
ACVR2B-AS1	NR_028389.1	n.247G>A		non_coding_transcript_exon_variant	Exon 1 of 2
ACVR2B	XM_017007515.3	c.-41C>T		5_prime_UTR_variant	Exon 1 of 11		XP_016863004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.52+200C>T		intron_variant	Intron 1 of 10	1	NM_001106.4	ENSP00000340361.3
ACVR2B-AS1	ENST00000441531.1	n.247G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
ACVR2B	ENST00000465020.5	n.56+200C>T		intron_variant	Intron 1 of 9	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

African (AFR) AF: 0.0943 AC: 592 AN: 6276

American (AMR) AF: 0.343 AC: 2016 AN: 5884

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 3594 AN: 7496

East Asian (EAS) AF: 0.331 AC: 6545 AN: 19744

South Asian (SAS) AF: 0.518 AC: 1434 AN: 2766

European-Finnish (FIN) AF: 0.547 AC: 10012 AN: 18314

Middle Eastern (MID) AF: 0.476 AC: 545 AN: 1146

European-Non Finnish (NFE) AF: 0.550 AC: 93936 AN: 170754

Other (OTH) AF: 0.457 AC: 6627 AN: 14504

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

African (AFR) AF: 0.0969 AC: 4026 AN: 41542

American (AMR) AF: 0.364 AC: 5574 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1668 AN: 3468

East Asian (EAS) AF: 0.268 AC: 1379 AN: 5136

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4820

European-Finnish (FIN) AF: 0.524 AC: 5548 AN: 10582

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.556 AC: 37782 AN: 67944

Other (OTH) AF: 0.414 AC: 874 AN: 2112

Alfa AF: 0.466 Hom.: 7664

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.7
DANN	Benign	0.85
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs3749386; hg19: chr3-38496065;