8-99965339-C-A

Variant names:

• chr8-99965339-C-A
• rs760451465
• NM_015668.5:c.3611G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015668.5(RGS22):​c.3611G>T​(p.Arg1204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1204Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RGS22 NM_015668.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 4 publications found

Genes affected

RGS22 (HGNC:24499): (regulator of G protein signaling 22) Enables G-protein alpha-subunit binding activity. Predicted to be involved in negative regulation of signal transduction. Located in actin cytoskeleton; cytosol; and fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18912622).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015668.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS22	NM_015668.5	MANE Select	c.3611G>T	p.Arg1204Leu	missense	Exon 24 of 28	NP_056483.3	Q8NE09-1
	RGS22	NM_001286692.2		c.3575G>T	p.Arg1192Leu	missense	Exon 24 of 28	NP_001273621.1	Q8NE09-3
	RGS22	NM_001286693.2		c.3068G>T	p.Arg1023Leu	missense	Exon 22 of 26	NP_001273622.1	G3V112

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS22	ENST00000360863.11	TSL:1 MANE Select	c.3611G>T	p.Arg1204Leu	missense	Exon 24 of 28	ENSP00000354109.6	Q8NE09-1
	RGS22	ENST00000523437.5	TSL:1	c.3575G>T	p.Arg1192Leu	missense	Exon 24 of 28	ENSP00000428212.1	Q8NE09-3
	RGS22	ENST00000870307.1		c.3452G>T	p.Arg1151Leu	missense	Exon 23 of 27	ENSP00000540366.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249138 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458432 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725762

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109116

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.090
Sift	Uncertain	0.010	D
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.60
MutPred		0.36		Loss of phosphorylation at T1207 (P = 0.0636)
MVP		0.55
MPC		0.067
ClinPred		0.27	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.31
Mutation Taster		=88/12	polymorphism

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: rs760451465; hg19: chr8-100977567; COSMIC: COSV62662536;