2-68782248-C-G

Position:

• chr2-68782248-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001007231.3(ARHGAP25):​c.277C>G​(p.Pro93Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP25 NM_001007231.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

Genes affected

ARHGAP25 (HGNC:28951): (Rho GTPase activating protein 25) ARHGAPs, such as ARHGAP25, encode negative regulators of Rho GTPases (see ARHA; MIM 165390), which are implicated in actin remodeling, cell polarity, and cell migration (Katoh and Katoh, 2004 [PubMed 15254788]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26787397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP25	NM_001007231.3	c.277C>G	p.Pro93Ala	missense_variant	3/11	ENST00000409202.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP25	ENST00000409202.8	c.277C>G	p.Pro93Ala	missense_variant	3/11	2	NM_001007231.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 03, 2022

The c.277C>G (p.P93A) alteration is located in exon 3 (coding exon 3) of the ARHGAP25 gene. This alteration results from a C to G substitution at nucleotide position 277, causing the proline (P) at amino acid position 93 to be replaced by an alanine (A). 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
BayesDel_addAF	Benign	-0.0091	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.0015
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.84	L;L;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.074	T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.70	P;.;P;.;P
Vest4		0.35
MutPred		0.50		Gain of catalytic residue at P93 (P = 0.0138);Gain of catalytic residue at P93 (P = 0.0138);.;.;.;
MVP		0.81
MPC		0.42
ClinPred		0.65	D
GERP RS		5.8
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1293246856; hg19: chr2-69009380;