chr5-76588909-G-C

Variant names:

• chr5-76588909-G-C
• rs1131232
• NM_006633.5:c.462G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006633.5(IQGAP2):​c.462G>C​(p.Leu154Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,136 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L154L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IQGAP2 NM_006633.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 0 publications found

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

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, 0.836

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.462G>C	p.Leu154Phe	missense	Exon 6 of 36	NP_006624.3	Q13576-1
	IQGAP2	NM_001285460.2		c.312G>C	p.Leu104Phe	missense	Exon 5 of 35	NP_001272389.2	F5H7S7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQGAP2	ENST00000274364.11	TSL:1 MANE Select	c.462G>C	p.Leu154Phe	missense	Exon 6 of 36	ENSP00000274364.6	Q13576-1
	IQGAP2	ENST00000514350.5	TSL:1	c.381G>C	p.Leu127Phe	missense	Exon 6 of 22	ENSP00000423672.1	D6R939
	IQGAP2	ENST00000379730.7	TSL:5	c.312G>C	p.Leu104Phe	missense	Exon 5 of 35	ENSP00000442313.2	F5H7S7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439136 Hom.: 0 Cov.: 25 AF XY: 0.00000139 AC XY: 1 AN XY: 717372

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

African (AFR) AF: 0.00 AC: 0 AN: 32704

American (AMR) AF: 0.00 AC: 0 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 85112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093508

Other (OTH) AF: 0.00 AC: 0 AN: 59476

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.11
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.60		Loss of catalytic residue at L154 (P = 0.0084)
MVP		0.87
MPC		0.44
ClinPred		0.99	D
GERP RS		-3.2
Varity_R		0.30
gMVP		0.66
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131232; hg19: chr5-75884734;