8-53946677-A-C

Position:

• chr8-53946677-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170587.4(RGS20):​c.672A>C​(p.Arg224Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGS20 NM_170587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

Genes affected

RGS20 (HGNC:14600): (regulator of G protein signaling 20) The protein encoded by this gene belongs to the family of regulator of G protein signaling (RGS) proteins, which are regulatory and structural components of G protein-coupled receptor complexes. RGS proteins inhibit signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound forms. This protein selectively binds to G(z)-alpha and G(alpha)-i2 subunits, and regulates their signaling activities. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS20	NM_170587.4	c.672A>C	p.Arg224Ser	missense_variant	4/6	ENST00000297313.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS20	ENST00000297313.8	c.672A>C	p.Arg224Ser	missense_variant	4/6	1	NM_170587.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

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

Jun 24, 2022

The c.672A>C (p.R224S) alteration is located in exon 4 (coding exon 4) of the RGS20 gene. This alteration results from a A to C substitution at nucleotide position 672, causing the arginine (R) at amino acid position 224 to be replaced by a serine (S). 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	0.75
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D;D;T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.025	D;T;T
Polyphen		0.61	P;P;B
Vest4		0.79
MutPred		0.33		Gain of glycosylation at R224 (P = 0.0545);.;.;
MVP		0.81
MPC		0.66
ClinPred		0.93	D
GERP RS		2.9
Varity_R		0.29
gMVP		0.72

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: rs1814489800; hg19: chr8-54859237;