2-147915329-A-G

Position:

chr2-147915329-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001616.5(ACVR2A):c.667A>G(p.Ile223Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACVR2A
NM_001616.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Variant links:

Genes affected

ACVR2A (HGNC:173): (activin A receptor type 2A) This gene encodes a receptor that mediates the functions of activins, which are members of the transforming growth factor-beta (TGF-beta) superfamily involved in diverse biological processes. The encoded protein is a transmembrane serine-threonine kinase receptor which mediates signaling by forming heterodimeric complexes with various combinations of type I and type II receptors and ligands in a cell-specific manner. The encoded type II receptor is primarily involved in ligand-binding and includes an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic serine-threonine kinase domain. This gene may be associated with susceptibility to preeclampsia, a pregnancy-related disease which can result in maternal and fetal morbidity and mortality. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jun 2013]

ACVR2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12628275).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2A	NM_001616.5 linkuse as main transcript	c.667A>G	p.Ile223Val	missense_variant	5/11	ENST00000241416.12	NP_001607.1	P27037-1
ACVR2A	NM_001278579.2 linkuse as main transcript	c.667A>G	p.Ile223Val	missense_variant	6/12		NP_001265508.1	P27037-1
ACVR2A	NM_001278580.2 linkuse as main transcript	c.343A>G	p.Ile115Val	missense_variant	5/11		NP_001265509.1	P27037-2
ACVR2A	XM_047446292.1 linkuse as main transcript	c.343A>G	p.Ile115Val	missense_variant	5/11		XP_047302248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACVR2A	ENST00000241416.12 linkuse as main transcript	c.667A>G	p.Ile223Val	missense_variant	5/11	1	NM_001616.5	ENSP00000241416.7	P27037-1
ACVR2A	ENST00000404590.1 linkuse as main transcript	c.667A>G	p.Ile223Val	missense_variant	6/12	1		ENSP00000384338.1	P27037-1
ACVR2A	ENST00000535787.5 linkuse as main transcript	c.343A>G	p.Ile115Val	missense_variant	5/11	2		ENSP00000439988.1	P27037-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250320

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459622

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.667A>G (p.I223V) alteration is located in exon 5 (coding exon 5) of the ACVR2A gene. This alteration results from a A to G substitution at nucleotide position 667, causing the isoleucine (I) at amino acid position 223 to be replaced by a valine (V). 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

0.068

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

.;T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.020

N;.;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.055

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.16

MutPred

0.30

Loss of ubiquitination at K226 (P = 0.0962);.;Loss of ubiquitination at K226 (P = 0.0962);

MVP

0.45

MPC

0.64

ClinPred

0.66

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over