2-218245465-C-T

Variant names:

• chr2-218245465-C-T
• rs1041935451
• NM_152862.3:c.595C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152862.3(ARPC2):​c.595C>T​(p.Leu199Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L199V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARPC2 NM_152862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152862.3. 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
	ARPC2	NM_152862.3	MANE Select	c.595C>T	p.Leu199Phe	missense	Exon 8 of 11	NP_690601.1	O15144
	ARPC2	NM_005731.3		c.595C>T	p.Leu199Phe	missense	Exon 7 of 10	NP_005722.1	Q53R19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC2	ENST00000315717.10	TSL:1 MANE Select	c.595C>T	p.Leu199Phe	missense	Exon 8 of 11	ENSP00000327137.5	O15144
	ARPC2	ENST00000295685.14	TSL:1	c.595C>T	p.Leu199Phe	missense	Exon 7 of 10	ENSP00000295685.10	O15144
	ARPC2	ENST00000943698.1		c.619C>T	p.Leu207Phe	missense	Exon 9 of 12	ENSP00000613757.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.93		Loss of disorder (P = 0.2001)
MVP		0.55
MPC		2.2
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.011	Neutral
Varity_R		0.73
gMVP		0.83
Mutation Taster		=43/57	disease causing

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: rs1041935451; hg19: chr2-219110188;