2-157538753-A-G

Position:

• chr2-157538753-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145259.3(ACVR1C):​c.1226-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,406,240 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (339 hom.)
• Consequence: ACVR1C NM_145259.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.310

Genes affected

ACVR1C (HGNC:18123): (activin A receptor type 1C) ACVR1C is a type I receptor for the TGFB (see MIM 190180) family of signaling molecules. Upon ligand binding, type I receptors phosphorylate cytoplasmic SMAD transcription factors, which then translocate to the nucleus and interact directly with DNA or in complex with other transcription factors (Bondestam et al., 2001 [PubMed 12063393]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-157538753-A-G is Benign according to our data. Variant chr2-157538753-A-G is described in ClinVar as [Benign]. Clinvar id is 1295039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR1C	NM_145259.3	c.1226-50T>C		intron_variant		ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2	c.1076-50T>C		intron_variant			NP_001104501.1
ACVR1C	NM_001111032.2	c.986-50T>C		intron_variant			NP_001104502.1
ACVR1C	NM_001111033.2	c.755-50T>C		intron_variant			NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13	c.1226-50T>C		intron_variant		1	NM_145259.3	ENSP00000243349	P1
ACVR1C	ENST00000335450.7	c.986-50T>C		intron_variant		1		ENSP00000335178
ACVR1C	ENST00000348328.9	c.755-50T>C		intron_variant		1		ENSP00000335139
ACVR1C	ENST00000409680.7	c.1076-50T>C		intron_variant		1		ENSP00000387168

Frequencies

GnomAD3 genomes AF: 0.00963 AC: 1464 AN: 152048 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0184 AC: 2813 AN: 153262 Hom.: 99 AF XY: 0.0162 AC XY: 1357 AN XY: 83882

Gnomad AFR exome AF: 0.000273

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0989

Gnomad SAS exome AF: 0.00463

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00643 AC: 8069 AN: 1254078 Hom.: 339 Cov.: 23 AF XY: 0.00622 AC XY: 3820 AN XY: 613918

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.00985

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.00378

Gnomad4 FIN exome AF: 0.0378

Gnomad4 NFE exome AF: 0.000592

Gnomad4 OTH exome AF: 0.00963

GnomAD4 genome AF: 0.00961 AC: 1462 AN: 152162 Hom.: 48 Cov.: 32 AF XY: 0.0121 AC XY: 903 AN XY: 74382

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.0958

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00439 Hom.: 2

Bravo AF: 0.00850

Asia WGS AF: 0.0480 AC: 166 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.7
DANN	Benign	0.82

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

Other links and lift over

dbSNP: rs75220520; hg19: chr2-158395265;