11-64727355-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/21 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 2758088.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP2	NM_001098671.2	c.1777C>T	p.Arg593Cys	missense_variant	16/17	ENST00000394432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP2	ENST00000394432.8	c.1777C>T	p.Arg593Cys	missense_variant	16/17	1	NM_001098671.2	P4

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

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251368 Hom.: 2 AF XY: 0.000500 AC XY: 68 AN XY: 135876

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 SAS exome AF: 0.00274

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.000232

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000113 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 06, 2024

Variant summary: RASGRP2 c.1777C>T (p.Arg593Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251368 control chromosomes in the gnomAD database, including 2 homozygotes. c.1777C>T has been reported in the literature in a heterozygous individual with features of platelet disorder (Puetz_2012). This report does not provide unequivocal conclusions about association of the variant with Platelet-Type Bleeding Disorder 18. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21815871). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	0.043
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;.;.;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.99	.;D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs144800583; hg19: chr11-64494827; COSMIC: COSV55458670; COSMIC: COSV55458670;