Genetic Variant ACVR2B:p.Cys16Trp (chr3-38454370-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001106.4(ACVR2B):c.48C>G(p.Cys16Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000891 in 1,122,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

ACVR2B
NM_001106.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

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]

ACVR2B links:

ACVR2B-AS1 (HGNC:44161): (ACVR2B antisense RNA 1)

ACVR2B-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4 link	c.48C>G	p.Cys16Trp	missense_variant	Exon 1 of 11	ENST00000352511.5	NP_001097.2	Q13705-1
ACVR2B-AS1	NR_028389.1 link	n.318+133G>C		intron_variant	Intron 1 of 1
ACVR2B	XM_017007515.3 link	c.-245C>G		upstream_gene_variant			XP_016863004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR2B	ENST00000352511.5 link	c.48C>G	p.Cys16Trp	missense_variant	Exon 1 of 11	1	NM_001106.4	ENSP00000340361.3	Q13705-1
ACVR2B	ENST00000465020.5 link	n.52C>G		non_coding_transcript_exon_variant	Exon 1 of 10	2
ACVR2B-AS1	ENST00000441531.1 link	n.318+133G>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.91e-7

AC:

AN:

1122290

Hom.:

Cov.:

AF XY:

0.00000186

AC XY:

AN XY:

538902

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:

0.00

Gnomad4 OTH exome

AF:

0.0000222

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.48C>G (p.C16W) alteration is located in exon 1 (coding exon 1) of the ACVR2B gene. This alteration results from a C to G substitution at nucleotide position 48, causing the cysteine (C) at amino acid position 16 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.38

Sift

Benign

0.18

Sift4G

Uncertain

0.044

Polyphen

0.91

Vest4

0.46

MutPred

0.34

Gain of MoRF binding (P = 0.0091);

MVP

0.86

MPC

1.2

ClinPred

0.87

GERP RS

2.7

Varity_R

0.24

gMVP

0.61

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over