NM_001098671.2:c.1777C>T

Variant names:

• chr11-64727355-G-A
• rs144800583
• NM_001098671.2:c.1777C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001098671.2(RASGRP2):​c.1777C>T​(p.Arg593Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,740 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R593H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (6 hom.)
• Consequence: RASGRP2 NM_001098671.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.94
• Publications: 4 publications found

Genes affected

RASGRP2 (HGNC:9879): (RAS guanyl releasing protein 2) The protein encoded by this gene is a brain-enriched nucleotide exchanged factor that contains an N-terminal GEF domain, 2 tandem repeats of EF-hand calcium-binding motifs, and a C-terminal diacylglycerol/phorbol ester-binding domain. This protein can activate small GTPases, including RAS and RAP1/RAS3. The nucleotide exchange activity of this protein can be stimulated by calcium and diacylglycerol. Four alternatively spliced transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

RASGRP2 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteopetrosis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0123511255).
• BP6: Variant 11-64727355-G-A is Benign according to our data. Variant chr11-64727355-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2758088.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000217 (33/152104) while in subpopulation SAS AF = 0.00312 (15/4814). AF 95% confidence interval is 0.00192. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098671.2. 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
	RASGRP2	NM_001098671.2	MANE Select	c.1777C>T	p.Arg593Cys	missense	Exon 16 of 17	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1867C>T	p.Arg623Cys	missense	Exon 17 of 18	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1864C>T	p.Arg622Cys	missense	Exon 17 of 18	NP_001427633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1777C>T	p.Arg593Cys	missense	Exon 16 of 17	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1777C>T	p.Arg593Cys	missense	Exon 16 of 17	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1777C>T	p.Arg593Cys	missense	Exon 16 of 17	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151986 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251368 AF XY: 0.000500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461636 Hom.: 6 Cov.: 31 AF XY: 0.000301 AC XY: 219 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00276 AC: 238 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111844

Other (OTH) AF: 0.000232 AC: 14 AN: 60384

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152104 Hom.: 1 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.51
MVP		0.32
MPC		0.95
ClinPred		0.063	T
GERP RS		2.6
Varity_R		0.14
gMVP		0.60
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs144800583; hg19: chr11-64494827; COSMIC: COSV55458670; COSMIC: COSV55458670;