3-38482193-C-T

Position:

• chr3-38482193-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000352511.5(ACVR2B):​c.1075-5C>T variant causes a splice region, splice polypyrimidine tract, 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 ENST00000352511.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002324
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.771

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 136290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38482193-C-T is described in Lovd as [Likely_benign]. Variant chr3-38482193-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 976 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.1075-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.1075-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001106.4	ENSP00000340361	P1
ACVR2B	ENST00000461232.1	n.4864-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
ACVR2B	ENST00000465020.5	n.1161-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.00670 AC: 1685 AN: 251410 Hom.: 7 AF XY: 0.00668 AC XY: 908 AN XY: 135884

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 SAS exome AF: 0.000784

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

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00809

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00980

Gnomad4 OTH exome AF: 0.00782

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

Gnomad4 AFR AF: 0.00186

Gnomad4 AMR AF: 0.00839

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00133

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0114

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

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ACVR2B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.28
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs115155428; hg19: chr3-38523684;