chr11-64735891-G-A

Variant names:

• chr11-64735891-G-A
• rs10897524
• NM_001098671.2:c.1173+12C>T

Variant summary

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

The NM_001440703.1(RASGRP2):​c.1260+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,609,534 control chromosomes in the GnomAD database, including 16,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2403 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13708 hom.)
• Consequence: RASGRP2 NM_001440703.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.02
• Publications: 14 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.88).
• BP6: Variant 11-64735891-G-A is Benign according to our data. Variant chr11-64735891-G-A is described in ClinVar as Benign. ClinVar VariationId is 403364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440703.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	NM_001098671.2	MANE Select	c.1173+12C>T		intron	N/A	NP_001092141.1
	RASGRP2	NM_001440703.1		c.1260+12C>T		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1260+12C>T		intron	N/A	NP_001427633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1173+12C>T		intron	N/A	ENSP00000377953.3
	RASGRP2	ENST00000354024.7	TSL:1	c.1173+12C>T		intron	N/A	ENSP00000338864.3
	RASGRP2	ENST00000377497.7	TSL:1	c.1173+12C>T		intron	N/A	ENSP00000366717.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24237 AN: 151974 Hom.: 2391 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0997

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.165 AC: 40850 AN: 247614 AF XY: 0.157

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0948

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.118 AC: 172357 AN: 1457442 Hom.: 13708 Cov.: 33 AF XY: 0.119 AC XY: 86139 AN XY: 725154

African (AFR) AF: 0.213 AC: 7095 AN: 33378

American (AMR) AF: 0.305 AC: 13536 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3726 AN: 26064

East Asian (EAS) AF: 0.409 AC: 16225 AN: 39630

South Asian (SAS) AF: 0.161 AC: 13869 AN: 85936

European-Finnish (FIN) AF: 0.112 AC: 5958 AN: 53224

Middle Eastern (MID) AF: 0.111 AC: 636 AN: 5738

European-Non Finnish (NFE) AF: 0.0932 AC: 103354 AN: 1108806

Other (OTH) AF: 0.132 AC: 7958 AN: 60246

GnomAD4 genome AF: 0.160 AC: 24302 AN: 152092 Hom.: 2403 Cov.: 32 AF XY: 0.164 AC XY: 12219 AN XY: 74362

African (AFR) AF: 0.209 AC: 8652 AN: 41454

American (AMR) AF: 0.257 AC: 3920 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2036 AN: 5164

South Asian (SAS) AF: 0.173 AC: 835 AN: 4828

European-Finnish (FIN) AF: 0.111 AC: 1179 AN: 10618

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0997 AC: 6779 AN: 67968

Other (OTH) AF: 0.159 AC: 335 AN: 2112

Alfa AF: 0.121 Hom.: 2543

Bravo AF: 0.175

Asia WGS AF: 0.280 AC: 974 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		-1.0
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: rs10897524; hg19: chr11-64503363; COSMIC: COSV62450335; COSMIC: COSV62450335;