5-76562544-C-T

Variant names:

• chr5-76562544-C-T
• rs376517879
• NM_006633.5:c.295C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_006633.5(IQGAP2):​c.295C>T​(p.Arg99Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,611,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: IQGAP2 NM_006633.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.34

Genes affected

IQGAP2 (HGNC:6111): (IQ motif containing GTPase activating protein 2) This gene encodes a member of the IQGAP family. The encoded protein contains three IQ domains, one calponin homology domain, one Ras-GAP domain and one WW domain. This protein interacts with components of the cytoskeleton, with cell adhesion molecules, and with several signaling molecules to regulate cell morphology and motility. It also acts as a tumor suppressor and has been found to play a role in regulating innate antiviral responses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQGAP2	NM_006633.5	c.295C>T	p.Arg99Cys	missense_variant	Exon 3 of 36	ENST00000274364.11	NP_006624.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQGAP2	ENST00000274364.11	c.295C>T	p.Arg99Cys	missense_variant	Exon 3 of 36	1	NM_006633.5	ENSP00000274364.6
IQGAP2	ENST00000514350.5	c.214C>T	p.Arg72Cys	missense_variant	Exon 3 of 22	1		ENSP00000423672.1
IQGAP2	ENST00000379730.7	c.145C>T	p.Arg49Cys	missense_variant	Exon 2 of 35	5		ENSP00000442313.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 249380 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 134808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1459762 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 726122

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295C>T (p.R99C) alteration is located in exon 3 (coding exon 3) of the IQGAP2 gene. This alteration results from a C to T substitution at nucleotide position 295, causing the arginine (R) at amino acid position 99 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.3	D;D;D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.86
MVP		0.97
MPC		0.83
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.75

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: rs376517879; hg19: chr5-75858369;