NM_001098671.2:c.1592-73A>G

Variant names:

• chr11-64729115-T-C
• rs559977
• NM_001098671.2:c.1592-73A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001098671.2(RASGRP2):​c.1592-73A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.983 in 1,463,354 control chromosomes in the GnomAD database, including 710,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (65127 hom., cov: 32)
  • Exomes 𝑓: 0.99 (645509 hom.)
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.701
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 11-64729115-T-C is Benign according to our data. Variant chr11-64729115-T-C is described in ClinVar as Benign. ClinVar VariationId is 1222996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.1592-73A>G		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1679-73A>G		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1679-73A>G		intron	N/A	NP_001427633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1592-73A>G		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1592-73A>G		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1592-73A>G		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.916 AC: 139303 AN: 152122 Hom.: 65091 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.970

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.926

GnomAD4 exome AF: 0.991 AC: 1299715 AN: 1311114 Hom.: 645509 AF XY: 0.993 AC XY: 646060 AN XY: 650930

African (AFR) AF: 0.710 AC: 21184 AN: 29838

American (AMR) AF: 0.983 AC: 35057 AN: 35652

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 24648 AN: 24732

East Asian (EAS) AF: 1.00 AC: 35583 AN: 35586

South Asian (SAS) AF: 0.999 AC: 77734 AN: 77788

European-Finnish (FIN) AF: 1.00 AC: 34530 AN: 34540

Middle Eastern (MID) AF: 0.988 AC: 5488 AN: 5554

European-Non Finnish (NFE) AF: 0.999 AC: 1010952 AN: 1011804

Other (OTH) AF: 0.981 AC: 54539 AN: 55620

GnomAD4 genome AF: 0.916 AC: 139404 AN: 152240 Hom.: 65127 Cov.: 32 AF XY: 0.918 AC XY: 68349 AN XY: 74420

African (AFR) AF: 0.708 AC: 29374 AN: 41494

American (AMR) AF: 0.970 AC: 14842 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3460 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67952 AN: 68030

Other (OTH) AF: 0.927 AC: 1959 AN: 2114

Alfa AF: 0.953 Hom.: 23412

Bravo AF: 0.905

Asia WGS AF: 0.984 AC: 3422 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.69
DANN	Benign	0.48
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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: rs559977; hg19: chr11-64496587;