Variant chr8-99996514-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015668.5(RGS22):c.2966T>C(p.Ile989Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RGS22
NM_015668.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.85

Variant links:

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]

RGS22 links:

RGS22 (HGNC:):

RGS22 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16386053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS22	NM_015668.5 linkuse as main transcript	c.2966T>C	p.Ile989Thr	missense_variant	20/28	ENST00000360863.11	NP_056483.3	Q8NE09-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RGS22	ENST00000360863.11 linkuse as main transcript	c.2966T>C	p.Ile989Thr	missense_variant	20/28	1	NM_015668.5	ENSP00000354109.6	Q8NE09-1
RGS22	ENST00000523437.5 linkuse as main transcript	c.2930T>C	p.Ile977Thr	missense_variant	20/28	1		ENSP00000428212.1	Q8NE09-3
RGS22	ENST00000523287.5 linkuse as main transcript	c.2423T>C	p.Ile808Thr	missense_variant	18/26	2		ENSP00000429382.1	G3V112
RGS22	ENST00000517769.5 linkuse as main transcript	n.1194T>C		non_coding_transcript_exon_variant	9/17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249094

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461112

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726874

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.2966T>C (p.I989T) alteration is located in exon 20 (coding exon 20) of the RGS22 gene. This alteration results from a T to C substitution at nucleotide position 2966, causing the isoleucine (I) at amino acid position 989 to be replaced by a threonine (T). 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

Benign

0.15

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0088

T;T;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.075

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Benign

0.10

Sift

Benign

0.11

T;.;D;T

Sift4G

Benign

0.098

T;T;T;T

Polyphen

0.16

B;.;B;.

Vest4

0.45

MutPred

0.48

Gain of disorder (P = 0.0276);.;.;.;

MVP

0.31

MPC

0.13

ClinPred

0.39

GERP RS

4.0

Varity_R

0.092

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over