NM_001616.5:c.11C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2A	NM_001616.5	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 11	NP_001607.1	P27037-1
	ACVR2A	NM_001278579.2		c.11C>T	p.Ala4Val	missense	Exon 2 of 12	NP_001265508.1	P27037-1
	ACVR2A	NM_001278580.2		c.-207+457C>T		intron	N/A	NP_001265509.1	P27037-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2A	ENST00000241416.12	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 11	ENSP00000241416.7	P27037-1
	ACVR2A	ENST00000404590.1	TSL:1	c.11C>T	p.Ala4Val	missense	Exon 2 of 12	ENSP00000384338.1	P27037-1
	ACVR2A	ENST00000943648.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 12	ENSP00000613707.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111974

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 26

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.34
Sift	Benign	0.079	T
Sift4G	Benign	0.12	T
Polyphen		0.65	P
Vest4		0.57
MutPred		0.30		Loss of disorder (P = 0.0775)
MVP		0.78
MPC		1.0
ClinPred		0.86	D
GERP RS		4.4
PromoterAI		0.0055	Neutral
Varity_R		0.12
gMVP		0.93
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1685273658; hg19: chr2-148602732;