17-2980313-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015085.5(RAP1GAP2):c.623G>A(p.Arg208Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00179 in 1,613,822 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: RAP1GAP2 NM_015085.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.59

Genes affected

RAP1GAP2 (HGNC:29176): (RAP1 GTPase activating protein 2) This gene encodes a GTPase-activating protein that activates the small guanine-nucleotide-binding protein Rap1 in platelets. The protein interacts with synaptotagmin-like protein 1 and Rab27 and regulates secretion of dense granules from platelets at sites of endothelial damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009512484).
• BP6: Variant 17-2980313-G-A is Benign according to our data. Variant chr17-2980313-G-A is described in ClinVar as [Benign]. Clinvar id is 768819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0092 (1400/152170) while in subpopulation AFR AF= 0.0317 (1317/41516). AF 95% confidence interval is 0.0303. There are 25 homozygotes in gnomad4. There are 640 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1GAP2	NM_015085.5	c.623G>A	p.Arg208Gln	missense_variant	9/25	ENST00000254695.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1GAP2	ENST00000254695.13	c.623G>A	p.Arg208Gln	missense_variant	9/25	1	NM_015085.5	P4

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1396 AN: 152052 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

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: 0.000265

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00246 AC: 612 AN: 249264 Hom.: 8 AF XY: 0.00182 AC XY: 246 AN XY: 135228

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00101 AC: 1483 AN: 1461652 Hom.: 15 Cov.: 32 AF XY: 0.000873 AC XY: 635 AN XY: 727104

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00920 AC: 1400 AN: 152170 Hom.: 25 Cov.: 32 AF XY: 0.00860 AC XY: 640 AN XY: 74380

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00161 Hom.: 4

Bravo AF: 0.0110

ESP6500AA AF: 0.0288 AC: 115

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00281 AC: 340

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.;T;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;.;D;D
MetaRNN	Benign	0.0095	T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
Polyphen		0.98, 0.99	.;.;D;D;D
Vest4		0.35, 0.36, 0.35, 0.37
MVP		0.49
MPC		0.74
ClinPred		0.031	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.83

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: rs75798518; hg19: chr17-2883607; COSMIC: COSV99057270;