5-76617830-C-G

Variant names:

• chr5-76617830-C-G
• rs1270688227
• NM_004101.4:c.877G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004101.4(F2RL2):​c.877G>C​(p.Asp293His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. D293Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: F2RL2 NM_004101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.50
• Publications: 6 publications found

Genes affected

F2RL2 (HGNC:3539): (coagulation factor II thrombin receptor like 2) This gene encodes a member of the protease-activated receptor (PAR) family which is a subfamily of the seven transmembrane G protein-coupled cell surface receptor family. The encoded protein acts as a cofactor in the thrombin-mediated cleavage and activation of the protease-activated receptor family member PAR4. The encoded protein plays an essential role in hemostasis and thrombosis. Alternate splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Feb 2012]

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26960647).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004101.4. 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
	F2RL2	NM_004101.4	MANE Select	c.877G>C	p.Asp293His	missense	Exon 2 of 2	NP_004092.1	O00254-1
	IQGAP2	NM_006633.5	MANE Select	c.1521+6647C>G		intron	N/A	NP_006624.3	Q13576-1
	F2RL2	NM_001256566.2		c.811G>C	p.Asp271His	missense	Exon 2 of 2	NP_001243495.1	O00254-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2RL2	ENST00000296641.5	TSL:1 MANE Select	c.877G>C	p.Asp293His	missense	Exon 2 of 2	ENSP00000296641.3	O00254-1
	IQGAP2	ENST00000274364.11	TSL:1 MANE Select	c.1521+6647C>G		intron	N/A	ENSP00000274364.6	Q13576-1
	IQGAP2	ENST00000396234.7	TSL:1	c.180+6647C>G		intron	N/A	ENSP00000379535.3	Q13576-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727112

⚠️ 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: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ 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	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	N
PhyloP100		4.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.29
MutPred		0.51		Gain of MoRF binding (P = 0.0513)
MVP		0.72
MPC		0.075
ClinPred		0.64	D
GERP RS		5.3
Varity_R		0.090
gMVP		0.46
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1270688227; hg19: chr5-75913655; COSMIC: COSV104569340;