Genetic Variant NM_006633.5:c.295C>A (chr5-76562544-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006633.5(IQGAP2):c.295C>A(p.Arg99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R99H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IQGAP2
NM_006633.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

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]

IQGAP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006633.5. 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
	IQGAP2	NM_006633.5	MANE Select	c.295C>A	p.Arg99Ser	missense	Exon 3 of 36	NP_006624.3	Q13576-1
	IQGAP2	NM_001285460.2		c.145C>A	p.Arg49Ser	missense	Exon 2 of 35	NP_001272389.2	F5H7S7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQGAP2	ENST00000274364.11	TSL:1 MANE Select	c.295C>A	p.Arg99Ser	missense	Exon 3 of 36	ENSP00000274364.6	Q13576-1
IQGAP2	ENST00000514350.5	TSL:1	c.214C>A	p.Arg72Ser	missense	Exon 3 of 22	ENSP00000423672.1	D6R939
IQGAP2	ENST00000379730.7	TSL:5	c.145C>A	p.Arg49Ser	missense	Exon 2 of 35	ENSP00000442313.2	F5H7S7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726122

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

44290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

85676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111230

Other (OTH)

AF:

0.00

AC:

AN:

60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.7

PhyloP100

3.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.64

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.91

MutPred

0.49

Loss of MoRF binding (P = 0.0318)

MVP

0.96

MPC

0.74

ClinPred

1.0

GERP RS

5.8

Varity_R

0.72

gMVP

0.78

Mutation Taster

=227/73

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over