2-147899762-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001616.5(ACVR2A):c.392C>G(p.Thr131Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: ACVR2A NM_001616.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACVR2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.24097243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR2A	NM_001616.5	c.392C>G	p.Thr131Arg	missense_variant	4/11	ENST00000241416.12
ACVR2A	NM_001278579.2	c.392C>G	p.Thr131Arg	missense_variant	5/12
ACVR2A	NM_001278580.2	c.68C>G	p.Thr23Arg	missense_variant	4/11
ACVR2A	XM_047446292.1	c.68C>G	p.Thr23Arg	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2A	ENST00000241416.12	c.392C>G	p.Thr131Arg	missense_variant	4/11	1	NM_001616.5	P1
	ENST00000402410.2	n.211-160G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 21, 2022

The c.392C>G (p.T131R) alteration is located in exon 4 (coding exon 4) of the ACVR2A gene. This alteration results from a C to G substitution at nucleotide position 392, causing the threonine (T) at amino acid position 131 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Benign	0.93
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	0.020
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.39
MutPred		0.28		Loss of glycosylation at T131 (P = 0.0011);.;Loss of glycosylation at T131 (P = 0.0011);
MVP		0.66
MPC		1.0
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.79

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.

Other links and lift over

hg19: chr2-148657331;