2-147845163-C-T

Variant names:

• chr2-147845163-C-T
• rs1685273658
• NM_001616.5:c.11C>T

Variant summary

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

The NM_001616.5(ACVR2A):​c.11C>T​(p.Ala4Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACVR2A NM_001616.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 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
ACVR2A	NM_001616.5	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 11	ENST00000241416.12	NP_001607.1
ACVR2A	NM_001278579.2	c.11C>T	p.Ala4Val	missense_variant	Exon 2 of 12		NP_001265508.1
ACVR2A	NM_001278580.2	c.-207+457C>T		intron_variant	Intron 1 of 10		NP_001265509.1
ACVR2A	XM_047446292.1	c.-270+457C>T		intron_variant	Intron 1 of 10		XP_047302248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR2A	ENST00000241416.12	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 11	1	NM_001616.5	ENSP00000241416.7

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461574 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727068

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 26

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>T (p.A4V) alteration is located in exon 1 (coding exon 1) of the ACVR2A gene. This alteration results from a C to T substitution at nucleotide position 11, causing the alanine (A) at amino acid position 4 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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.27	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.079	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.65	P;P
Vest4		0.57
MutPred		0.30		Loss of disorder (P = 0.0775);Loss of disorder (P = 0.0775);
MVP		0.78
MPC		1.0
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.12
gMVP		0.93

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: rs1685273658; hg19: chr2-148602732;