2-218249834-C-T

Position:

• chr2-218249834-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152862.3(ARPC2):​c.791C>T​(p.Thr264Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ARPC2 NM_152862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ARPC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC2	NM_152862.3	c.791C>T	p.Thr264Ile	missense_variant	10/11	ENST00000315717.10	NP_690601.1
ARPC2	NM_005731.3	c.791C>T	p.Thr264Ile	missense_variant	9/10		NP_005722.1
ARPC2	XM_017003113.2	c.626C>T	p.Thr209Ile	missense_variant	9/10		XP_016858602.1
ARPC2	XM_047442808.1	c.449C>T	p.Thr150Ile	missense_variant	6/7		XP_047298764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC2	ENST00000315717.10	c.791C>T	p.Thr264Ile	missense_variant	10/11	1	NM_152862.3	ENSP00000327137.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.791C>T (p.T264I) 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 791, causing the threonine (T) at amino acid position 264 to be replaced by an isoleucine (I). 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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;T
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.46	P;P;.
Vest4		0.84
MutPred		0.69		Loss of methylation at K259 (P = 0.0694);Loss of methylation at K259 (P = 0.0694);.;
MVP		0.70
MPC		2.0
ClinPred		0.93	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.95

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: rs1690140171; hg19: chr2-219114557;