1-192184489-C-G

Variant names:

• chr1-192184489-C-G
• rs868020301
• NM_130782.3:c.643C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_130782.3(RGS18):​c.643C>G​(p.Arg215Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,459,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RGS18 NM_130782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.882

Genes affected

RGS18 (HGNC:14261): (regulator of G protein signaling 18) This gene encodes a member of the regulator of G-protein signaling family. This protein is contains a conserved, 120 amino acid motif called the RGS domain. The protein attenuates the signaling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38427567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS18	NM_130782.3	c.643C>G	p.Arg215Gly	missense_variant	Exon 5 of 5	ENST00000367460.4	NP_570138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS18	ENST00000367460.4	c.643C>G	p.Arg215Gly	missense_variant	Exon 5 of 5	1	NM_130782.3	ENSP00000356430.3
ENSG00000285280	ENST00000643151.1	n.558G>C		non_coding_transcript_exon_variant	Exon 7 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459746 Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19 AN XY: 726258

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643C>G (p.R215G) alteration is located in exon 5 (coding exon 5) of the RGS18 gene. This alteration results from a C to G substitution at nucleotide position 643, causing the arginine (R) at amino acid position 215 to be replaced by a glycine (G). 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	Benign	0.00086	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.49		Loss of stability (P = 0.0236);
MVP		0.83
MPC		0.32
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.38
gMVP		0.60

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: rs868020301; hg19: chr1-192153619;