5-76570598-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_006633.5(IQGAP2):c.322C>T(p.Arg108Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000377 in 1,613,104 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: IQGAP2 NM_006633.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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.

• PM4: Stoplost variant in NM_006633.5 Downstream stopcodon found after 1662 codons.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQGAP2	NM_006633.5	c.322C>T	p.Arg108Ter	stop_gained	4/36	ENST00000274364.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQGAP2	ENST00000274364.11	c.322C>T	p.Arg108Ter	stop_gained	4/36	1	NM_006633.5	P1
IQGAP2	ENST00000514350.5	c.241C>T	p.Arg81Ter	stop_gained	4/22	1
IQGAP2	ENST00000379730.7	c.172C>T	p.Arg58Ter	stop_gained	3/35	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251364 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1460994 Hom.: 0 Cov.: 29 AF XY: 0.000392 AC XY: 285 AN XY: 726886

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000506

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74310

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000119

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

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;D
Vest4		0.80
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs192694811; hg19: chr5-75866423; COSMIC: COSV57168838;