chr1-192811492-T-C

Position:

• chr1-192811492-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002923.4(RGS2):​c.532T>C​(p.Tyr178His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RGS2 NM_002923.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

ENSG00000285280 (HGNC:49018): (RSG2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS2	NM_002923.4	c.532T>C	p.Tyr178His	missense_variant	5/5	ENST00000235382.7	NP_002914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS2	ENST00000235382.7	c.532T>C	p.Tyr178His	missense_variant	5/5	1	NM_002923.4	ENSP00000235382.5
ENSG00000285280	ENST00000644058.1	n.194-45298A>G		intron_variant
ENSG00000285280	ENST00000644134.1	n.105-45298A>G		intron_variant
ENSG00000285280	ENST00000645822.1	n.199+15412A>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.532T>C (p.Y178H) alteration is located in exon 5 (coding exon 5) of the RGS2 gene. This alteration results from a T to C substitution at nucleotide position 532, causing the tyrosine (Y) at amino acid position 178 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.53
Sift	Benign	0.26	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.76		Gain of disorder (P = 0.0512);
MVP		0.98
MPC		0.42
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-192780622;