8-99965427-C-A

Variant names:

• chr8-99965427-C-A
• rs187452253
• NM_015668.5:c.3523G>T

Variant summary

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

The NM_015668.5(RGS22):​c.3523G>T​(p.Gly1175*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RGS22 NM_015668.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 1 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 2 ACMG points.

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

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.3523G>T	p.Gly1175*	stop_gained	Exon 24 of 28	NP_056483.3	Q8NE09-1
	RGS22	NM_001286692.2		c.3487G>T	p.Gly1163*	stop_gained	Exon 24 of 28	NP_001273621.1	Q8NE09-3
	RGS22	NM_001286693.2		c.2980G>T	p.Gly994*	stop_gained	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.3523G>T	p.Gly1175*	stop_gained	Exon 24 of 28	ENSP00000354109.6	Q8NE09-1
	RGS22	ENST00000523437.5	TSL:1	c.3487G>T	p.Gly1163*	stop_gained	Exon 24 of 28	ENSP00000428212.1	Q8NE09-3
	RGS22	ENST00000870307.1		c.3364G>T	p.Gly1122*	stop_gained	Exon 23 of 27	ENSP00000540366.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444652 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 719194

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85038

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098266

Other (OTH) AF: 0.00 AC: 0 AN: 59776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Benign	0.97
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.60	D
PhyloP100		1.0
Vest4		0.25
GERP RS		3.3
Mutation Taster		=19/181	disease causing (fs/PTC)

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: rs187452253; hg19: chr8-100977655;