10-48450715-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021226.4(ARHGAP22):c.1414C>T(p.Arg472Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,402,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ARHGAP22 NM_021226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

Genes affected

ARHGAP22 (HGNC:30320): (Rho GTPase activating protein 22) This gene encodes a member of the GTPase activating protein family which activates a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues. The result of these interactions is regulation of cell motility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25190282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP22	NM_021226.4	c.1414C>T	p.Arg472Cys	missense_variant	9/10	ENST00000249601.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP22	ENST00000249601.9	c.1414C>T	p.Arg472Cys	missense_variant	9/10	1	NM_021226.4	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 158016 Hom.: 0 AF XY: 0.0000119 AC XY: 1 AN XY: 84080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000858

Gnomad SAS exome AF: 0.0000438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1402166 Hom.: 0 Cov.: 36 AF XY: 0.00000433 AC XY: 3 AN XY: 692056

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.0000275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000175 AC: 2

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 30, 2021

The c.1414C>T (p.R472C) alteration is located in exon 9 (coding exon 9) of the ARHGAP22 gene. This alteration results from a C to T substitution at nucleotide position 1414, causing the arginine (R) at amino acid position 472 to be replaced by a cysteine (C). 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	Benign	0.087
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;.;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;T;T;T;T;D;D
Polyphen		1.0	D;D;.;.;D;.;B
Vest4		0.23
MutPred		0.43		Loss of MoRF binding (P = 0.0151);.;.;.;.;.;.;
MVP		0.42
MPC		0.80
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.53
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs777718892; hg19: chr10-49658758; COSMIC: COSV99984611; COSMIC: COSV99984611;