NM_001106.4:c.48C>G

Variant names:

• chr3-38454370-C-G
• NM_001106.4:c.48C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001106.4(ACVR2B):​c.48C>G​(p.Cys16Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000891 in 1,122,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: ACVR2B NM_001106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65
• Publications: 0 publications found

Genes affected

ACVR2B (HGNC:174): (activin A receptor type 2B) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Type II receptors are considered to be constitutively active kinases. This gene encodes activin A type IIB receptor, which displays a 3- to 4-fold higher affinity for the ligand than activin A type II receptor. [provided by RefSeq, Jul 2008]

ACVR2B-AS1 (HGNC:44161): (ACVR2B antisense RNA 1)

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_001106.4. 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
	ACVR2B	NM_001106.4	MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 11	NP_001097.2	Q13705-1
	ACVR2B-AS1	NR_028389.1		n.318+133G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	ENST00000352511.5	TSL:1 MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 11	ENSP00000340361.3	Q13705-1
	ACVR2B	ENST00000922132.1		c.48C>G	p.Cys16Trp	missense	Exon 1 of 11	ENSP00000592191.1
	ACVR2B	ENST00000465020.5	TSL:2	n.52C>G		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.91e-7 AC: 1 AN: 1122290 Hom.: 0 Cov.: 30 AF XY: 0.00000186 AC XY: 1 AN XY: 538902

African (AFR) AF: 0.00 AC: 0 AN: 23128

American (AMR) AF: 0.00 AC: 0 AN: 9854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15488

East Asian (EAS) AF: 0.00 AC: 0 AN: 26694

South Asian (SAS) AF: 0.00 AC: 0 AN: 30928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 944310

Other (OTH) AF: 0.0000222 AC: 1 AN: 45076

GnomAD4 genome Cov.: 31

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	Benign	0.17
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.18	T
Sift4G	Uncertain	0.044	D
Polyphen		0.91	P
Vest4		0.46
MutPred		0.34		Gain of MoRF binding (P = 0.0091)
MVP		0.86
MPC		1.2
ClinPred		0.87	D
GERP RS		2.7
PromoterAI		0.019	Neutral
Varity_R		0.24
gMVP		0.61
Mutation Taster		=48/52	disease causing

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

Other links and lift over

hg19: chr3-38495861;