2-147927213-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001616.5(ACVR2A):c.1481T>C(p.Ile494Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,612,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ACVR2A
NM_001616.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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 -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, ACVR2A

BP4

Computational evidence support a benign effect (MetaRNN=0.23974738).

BS2

High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACVR2A	NM_001616.5 linkuse as main transcript	c.1481T>C	p.Ile494Thr	missense_variant	11/11	ENST00000241416.12
ACVR2A	NM_001278579.2 linkuse as main transcript	c.1481T>C	p.Ile494Thr	missense_variant	12/12
ACVR2A	NM_001278580.2 linkuse as main transcript	c.1157T>C	p.Ile386Thr	missense_variant	11/11
ACVR2A	XM_047446292.1 linkuse as main transcript	c.1157T>C	p.Ile386Thr	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2A	ENST00000241416.12 linkuse as main transcript	c.1481T>C	p.Ile494Thr	missense_variant	11/11	1	NM_001616.5	P1	P27037-1
ACVR2A	ENST00000404590.1 linkuse as main transcript	c.1481T>C	p.Ile494Thr	missense_variant	12/12	1		P1	P27037-1
ACVR2A	ENST00000535787.5 linkuse as main transcript	c.1157T>C	p.Ile386Thr	missense_variant	11/11	2			P27037-2
ACVR2A	ENST00000495775.1 linkuse as main transcript	n.609T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000680

AC:

AN:

249906

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135054

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000436

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460180

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726384

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000404

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151902

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000577

AC:

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 23, 2023

The c.1481T>C (p.I494T) alteration is located in exon 11 (coding exon 11) of the ACVR2A gene. This alteration results from a T to C substitution at nucleotide position 1481, causing the isoleucine (I) at amino acid position 494 to be replaced by a threonine (T). 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

0.24

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.060

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.022

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.8

L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.34

N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.13

B;.;B

Vest4

0.55

MutPred

0.58

Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);

MVP

0.92

MPC

1.5

ClinPred

0.095

GERP RS

6.0

Varity_R

0.14

gMVP

0.95

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