2-68813348-C-T

Variant names:

• chr2-68813348-C-T
• NM_001007231.3:c.736C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001007231.3(ARHGAP25):​c.736C>T​(p.Pro246Ser) 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. 12/20 in silico tools predict a damaging 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: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007231.3. 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
	ARHGAP25	NM_001007231.3	MANE Select	c.736C>T	p.Pro246Ser	missense	Exon 6 of 11	NP_001007232.2	P42331-4
	ARHGAP25	NM_001364819.1		c.733C>T	p.Pro245Ser	missense	Exon 6 of 11	NP_001351748.1	P42331-1
	ARHGAP25	NM_001166276.2		c.715C>T	p.Pro239Ser	missense	Exon 5 of 10	NP_001159748.1	P42331-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP25	ENST00000409202.8	TSL:2 MANE Select	c.736C>T	p.Pro246Ser	missense	Exon 6 of 11	ENSP00000386911.3	P42331-4
	ARHGAP25	ENST00000409220.5	TSL:1	c.715C>T	p.Pro239Ser	missense	Exon 5 of 10	ENSP00000386241.1	P42331-6
	ARHGAP25	ENST00000409030.7	TSL:1	c.712C>T	p.Pro238Ser	missense	Exon 5 of 10	ENSP00000386863.3	P42331-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.36	T
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.81
MPC		0.91
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.78
Mutation Taster		=25/75	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

hg19: chr2-69040480;