2-218249884-C-T

Variant names:

• chr2-218249884-C-T
• rs1267492794
• NM_152862.3:c.841C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_152862.3(ARPC2):​c.841C>T​(p.Arg281Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ARPC2 NM_152862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

Genes affected

ARPC2 (HGNC:705): (actin related protein 2/3 complex subunit 2) This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been implicated in the control of actin polymerization in cells and has been conserved through evolution. The exact role of the protein encoded by this gene, the p34 subunit, has yet to be determined. Two alternatively spliced variants have been characterized to date. Additional alternatively spliced variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARPC2	NM_152862.3	c.841C>T	p.Arg281Cys	missense_variant	Exon 10 of 11	ENST00000315717.10	NP_690601.1
ARPC2	NM_005731.3	c.841C>T	p.Arg281Cys	missense_variant	Exon 9 of 10		NP_005722.1
ARPC2	XM_017003113.2	c.676C>T	p.Arg226Cys	missense_variant	Exon 9 of 10		XP_016858602.1
ARPC2	XM_047442808.1	c.499C>T	p.Arg167Cys	missense_variant	Exon 6 of 7		XP_047298764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARPC2	ENST00000315717.10	c.841C>T	p.Arg281Cys	missense_variant	Exon 10 of 11	1	NM_152862.3	ENSP00000327137.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250326 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135254

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461390 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726922

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841C>T (p.R281C) alteration is located in exon 10 (coding exon 9) of the ARPC2 gene. This alteration results from a C to T substitution at nucleotide position 841, causing the arginine (R) at amino acid position 281 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.89
MutPred		0.67		Loss of MoRF binding (P = 0.009);Loss of MoRF binding (P = 0.009);.;
MVP		0.67
MPC		1.4
ClinPred		0.90	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1267492794; hg19: chr2-219114607;