5-76618519-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004101.4(F2RL2):c.188C>T(p.Thr63Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: F2RL2 NM_004101.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.929

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044506192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F2RL2	NM_004101.4	c.188C>T	p.Thr63Met	missense_variant	2/2	ENST00000296641.5
IQGAP2	NM_006633.5	c.1521+7336G>A		intron_variant		ENST00000274364.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F2RL2	ENST00000296641.5	c.188C>T	p.Thr63Met	missense_variant	2/2	1	NM_004101.4	P2
IQGAP2	ENST00000274364.11	c.1521+7336G>A		intron_variant		1	NM_006633.5	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251150 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135786

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.0000743 AC XY: 54 AN XY: 727240

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74442

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Ambry Genetics

Nov 17, 2022

The c.188C>T (p.T63M) alteration is located in exon 2 (coding exon 2) of the F2RL2 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the threonine (T) at amino acid position 63 to be replaced by a methionine (M). 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	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D;T
Sift4G	Uncertain	0.020	D;D
Polyphen		0.89	P;.
Vest4		0.19
MVP		0.64
MPC		0.15
ClinPred		0.012	T
GERP RS		2.0
Varity_R		0.023
gMVP		0.49

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: rs372087578; hg19: chr5-75914344; COSMIC: COSV56970061;