rs17692648

Variant names:

• chr2-147930162-A-C
• rs17692648
• NM_001616.5:c.*2888A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001616.5(ACVR2A):​c.*2888A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,358 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1700 hom., cov: 31)
  • Exomes 𝑓: 0.090 (5 hom.)
• Consequence: ACVR2A NM_001616.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 15 publications found

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]

ORC4 (HGNC:8490): (origin recognition complex subunit 4) The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2A	NM_001616.5	MANE Select	c.*2888A>C		3_prime_UTR	Exon 11 of 11	NP_001607.1
	ACVR2A	NM_001278579.2		c.*2888A>C		3_prime_UTR	Exon 12 of 12	NP_001265508.1
	ACVR2A	NM_001278580.2		c.*2888A>C		3_prime_UTR	Exon 11 of 11	NP_001265509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2A	ENST00000241416.12	TSL:1 MANE Select	c.*2888A>C		3_prime_UTR	Exon 11 of 11	ENSP00000241416.7
	ACVR2A	ENST00000535787.5	TSL:2	c.*2888A>C		3_prime_UTR	Exon 11 of 11	ENSP00000439988.1
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.*5348T>G		downstream_gene	N/A	ENSP00000376597.5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20633 AN: 151808 Hom.: 1699 Cov.: 31

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0971

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0889

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.0903 AC: 39 AN: 432 Hom.: 5 Cov.: 0 AF XY: 0.0808 AC XY: 21 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0915 AC: 39 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.136 AC: 20630 AN: 151926 Hom.: 1700 Cov.: 31 AF XY: 0.132 AC XY: 9774 AN XY: 74272

African (AFR) AF: 0.0611 AC: 2532 AN: 41472

American (AMR) AF: 0.124 AC: 1883 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3468

East Asian (EAS) AF: 0.0967 AC: 500 AN: 5170

South Asian (SAS) AF: 0.151 AC: 730 AN: 4820

European-Finnish (FIN) AF: 0.0889 AC: 940 AN: 10568

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12450 AN: 67904

Other (OTH) AF: 0.148 AC: 312 AN: 2108

Alfa AF: 0.171 Hom.: 6977

Bravo AF: 0.134

Asia WGS AF: 0.121 AC: 418 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.74
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17692648; hg19: chr2-148687731;