2-143202194-G-C

Variant names:

• chr2-143202194-G-C
• rs758074426
• NM_018460.4:c.226G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018460.4(ARHGAP15):​c.226G>C​(p.Glu76Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. E76K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGAP15 NM_018460.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

ARHGAP15 (HGNC:21030): (Rho GTPase activating protein 15) RHO GTPases (see ARHA; MIM 165390) regulate diverse biologic processes, and their activity is regulated by RHO GTPase-activating proteins (GAPs), such as ARHGAP15 (Seoh et al., 2003 [PubMed 12650940]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14122346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018460.4. 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
	ARHGAP15	NM_018460.4	MANE Select	c.226G>C	p.Glu76Gln	missense	Exon 3 of 14	NP_060930.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP15	ENST00000295095.11	TSL:1 MANE Select	c.226G>C	p.Glu76Gln	missense	Exon 3 of 14	ENSP00000295095.6	Q53QZ3
	ARHGAP15	ENST00000906468.1		c.226G>C	p.Glu76Gln	missense	Exon 3 of 15	ENSP00000576527.1
	ARHGAP15	ENST00000906471.1		c.226G>C	p.Glu76Gln	missense	Exon 3 of 14	ENSP00000576530.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250166 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458872 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725944

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109630

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.025
Sift	Benign	0.091	T
Sift4G	Benign	0.16	T
Polyphen		0.012	B
Vest4		0.25
MutPred		0.39		Gain of sheet (P = 0.0827)
MVP		0.41
MPC		0.064
ClinPred		0.25	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.31
Mutation Taster		=91/9	polymorphism

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: rs758074426; hg19: chr2-143959763; COSMIC: COSV54513567;