1-192809139-G-A

Position:

• chr1-192809139-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002923.4(RGS2):​c.68G>A​(p.Gly23Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,613,910 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (2 hom.)
• Consequence: RGS2 NM_002923.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.20

Genes affected

RGS2 (HGNC:9998): (regulator of G protein signaling 2) Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 2 belongs to this family. The protein acts as a mediator of myeloid differentiation and may play a role in leukemogenesis. [provided by RefSeq, Aug 2009]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07001865).
• BS2: High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS2	NM_002923.4	c.68G>A	p.Gly23Asp	missense_variant	1/5	ENST00000235382.7	NP_002914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS2	ENST00000235382.7	c.68G>A	p.Gly23Asp	missense_variant	1/5	1	NM_002923.4	ENSP00000235382	P1
	ENST00000644134.1	n.105-42945C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000704 AC: 107 AN: 152092 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251458 Hom.: 0 AF XY: 0.000692 AC XY: 94 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000750 AC: 1097 AN: 1461698 Hom.: 2 Cov.: 30 AF XY: 0.000778 AC XY: 566 AN XY: 727176

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000743

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152212 Hom.: 2 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74420

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000974 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Noe 2010 reported this variant in the heterozygous state in 3 related patients with Platelet Gs hypofunction. In vitro assays suggest Gs signaling defect. Variant not in ClinVar. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.19	N
REVEL	Uncertain	0.30
Sift	Benign	0.36	T
Sift4G	Benign	0.63	T
Polyphen		0.010	B
Vest4		0.75
MVP		0.92
MPC		0.074
ClinPred		0.0099	T
GERP RS		3.4
Varity_R		0.085
gMVP		0.23

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: rs148489044; hg19: chr1-192778269; COSMIC: COSV52458746; COSMIC: COSV52458746;