NM_001106.4:c.1075-5C>T

Variant names:

• chr3-38482193-C-T
• rs115155428
• NM_001106.4:c.1075-5C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001106.4(ACVR2B):​c.1075-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,613,656 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (5 hom., cov: 29)
  • Exomes 𝑓: 0.0084 (64 hom.)
• Consequence: ACVR2B NM_001106.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002324
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.771
• Publications: 1 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 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 4, autosomal

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-38482193-C-T is Benign according to our data. Variant chr3-38482193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 976 AD gene.

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.1075-5C>T		splice_region intron	N/A	NP_001097.2	Q13705-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	ENST00000352511.5	TSL:1 MANE Select	c.1075-5C>T		splice_region intron	N/A	ENSP00000340361.3	Q13705-1
	ACVR2B	ENST00000461232.1	TSL:1	n.4864-5C>T		splice_region intron	N/A
	ACVR2B	ENST00000922132.1		c.1051-5C>T		splice_region intron	N/A	ENSP00000592191.1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 976 AN: 151678 Hom.: 5 Cov.: 29

Gnomad AFR AF: 0.00187

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00670 AC: 1685 AN: 251410 AF XY: 0.00668

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00840 AC: 12284 AN: 1461860 Hom.: 64 Cov.: 32 AF XY: 0.00842 AC XY: 6121 AN XY: 727230

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00809 AC: 362 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 205 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00143 AC: 123 AN: 86256

European-Finnish (FIN) AF: 0.00172 AC: 92 AN: 53416

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.00980 AC: 10895 AN: 1111994

Other (OTH) AF: 0.00782 AC: 472 AN: 60390

GnomAD4 genome AF: 0.00643 AC: 976 AN: 151796 Hom.: 5 Cov.: 29 AF XY: 0.00603 AC XY: 447 AN XY: 74182

African (AFR) AF: 0.00186 AC: 77 AN: 41342

American (AMR) AF: 0.00839 AC: 128 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4774

European-Finnish (FIN) AF: 0.00133 AC: 14 AN: 10544

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 698 AN: 67936

Other (OTH) AF: 0.0114 AC: 24 AN: 2106

Alfa AF: 0.00799 Hom.: 2

Bravo AF: 0.00685

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Heterotaxy, visceral, 4, autosomal (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.28
DANN	Benign	0.69
PhyloP100		-0.77
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs115155428; hg19: chr3-38523684;