rs12452285

Positions:

• chr17-65193569-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262406.10(RGS9):​c.773C>T​(p.Ser258Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,613,216 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0050 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (124 hom.)
• Consequence: RGS9 ENST00000262406.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.773

Genes affected

RGS9 (HGNC:10004): (regulator of G protein signaling 9) This gene encodes a member of the RGS family of GTPase activating proteins that function in various signaling pathways by accelerating the deactivation of G proteins. This protein is anchored to photoreceptor membranes in retinal cells and deactivates G proteins in the rod and cone phototransduction cascades. Mutations in this gene result in bradyopsia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018083751).
• BP6: Variant 17-65193569-C-T is Benign according to our data. Variant chr17-65193569-C-T is described in ClinVar as [Benign]. Clinvar id is 167593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00505 (769/152292) while in subpopulation EAS AF= 0.0338 (175/5178). AF 95% confidence interval is 0.0297. There are 14 homozygotes in gnomad4. There are 446 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS9	NM_003835.4	c.773C>T	p.Ser258Leu	missense_variant	12/19	ENST00000262406.10	NP_003826.2
RGS9	NM_001081955.3	c.764C>T	p.Ser255Leu	missense_variant	12/19		NP_001075424.1
RGS9	NM_001165933.2	c.764C>T	p.Ser255Leu	missense_variant	12/17		NP_001159405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10	c.773C>T	p.Ser258Leu	missense_variant	12/19	1	NM_003835.4	ENSP00000262406	P4

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 757 AN: 152174 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00928 AC: 2316 AN: 249562 Hom.: 37 AF XY: 0.0105 AC XY: 1426 AN XY: 135390

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.0270

Gnomad SAS exome AF: 0.0343

Gnomad FIN exome AF: 0.00955

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00516 AC: 7543 AN: 1460924 Hom.: 124 Cov.: 30 AF XY: 0.00601 AC XY: 4366 AN XY: 726842

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.0402

Gnomad4 SAS exome AF: 0.0342

Gnomad4 FIN exome AF: 0.00917

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00505 AC: 769 AN: 152292 Hom.: 14 Cov.: 32 AF XY: 0.00599 AC XY: 446 AN XY: 74466

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.0338

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00418 Hom.: 18

Bravo AF: 0.00369

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000739 AC: 3

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.00951 AC: 1150

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00338

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.1
DANN	Benign	0.80
DEOGEN2	Benign	0.022	T;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.24	.;.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	.;.;N;N
REVEL	Benign	0.0080
Sift	Benign	0.53	.;.;T;T
Sift4G	Benign	0.36	.;T;T;T
Polyphen		0.0040, 0.0050	.;.;B;B
Vest4		0.14, 0.13, 0.14
MVP		0.30
MPC		0.16
ClinPred		0.0023	T
GERP RS		-2.4
Varity_R		0.067
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12452285; hg19: chr17-63189687; COSMIC: COSV52225553;