chr3-38477295-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001106.4(ACVR2B):​c.61C>T​(p.Arg21Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACVR2B
NM_001106.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32396042).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACVR2BNM_001106.4 linkuse as main transcriptc.61C>T p.Arg21Cys missense_variant 2/11 ENST00000352511.5 NP_001097.2 Q13705-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACVR2BENST00000352511.5 linkuse as main transcriptc.61C>T p.Arg21Cys missense_variant 2/111 NM_001106.4 ENSP00000340361.3 Q13705-1
ACVR2BENST00000461232.1 linkuse as main transcriptn.3850C>T non_coding_transcript_exon_variant 1/101
ACVR2BENST00000465020.5 linkuse as main transcriptn.65C>T non_coding_transcript_exon_variant 2/102

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461776
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ACVR2B-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 21, 2022The ACVR2B c.61C>T variant is predicted to result in the amino acid substitution p.Arg21Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.32
T
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
0.98
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.66
N
REVEL
Benign
0.27
Sift
Uncertain
0.015
D
Sift4G
Benign
0.18
T
Polyphen
0.92
P
Vest4
0.30
MutPred
0.34
Loss of disorder (P = 0.0325);
MVP
0.72
MPC
1.4
ClinPred
0.70
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.15
gMVP
0.57

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1409388869; hg19: chr3-38518786; API