2-147915329-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACVR2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.12628275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR2A	NM_001616.5	c.667A>G	p.Ile223Val	missense_variant	5/11	ENST00000241416.12
ACVR2A	NM_001278579.2	c.667A>G	p.Ile223Val	missense_variant	6/12
ACVR2A	NM_001278580.2	c.343A>G	p.Ile115Val	missense_variant	5/11
ACVR2A	XM_047446292.1	c.343A>G	p.Ile115Val	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2A	ENST00000241416.12	c.667A>G	p.Ile223Val	missense_variant	5/11	1	NM_001616.5	P1
ACVR2A	ENST00000404590.1	c.667A>G	p.Ile223Val	missense_variant	6/12	1		P1
ACVR2A	ENST00000535787.5	c.343A>G	p.Ile115Val	missense_variant	5/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250320 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135276

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: 6 AN: 1459622 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726086

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.: 32

Alfa AF: 0.0000624 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.020	N;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
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	D
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

Other links and lift over

dbSNP: rs1489499469; hg19: chr2-148672898;