chr17-65137556-C-A

Position:

• chr17-65137556-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003835.4(RGS9):​c.16C>A​(p.Gln6Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGS9 NM_003835.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.61

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 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=0.22538078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS9	NM_003835.4	c.16C>A	p.Gln6Lys	missense_variant	1/19	ENST00000262406.10	NP_003826.2
RGS9	NM_001081955.3	c.16C>A	p.Gln6Lys	missense_variant	1/19		NP_001075424.1
RGS9	NM_001165933.2	c.16C>A	p.Gln6Lys	missense_variant	1/17		NP_001159405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10	c.16C>A	p.Gln6Lys	missense_variant	1/19	1	NM_003835.4	ENSP00000262406	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248670 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134966

Gnomad AFR exome AF: 0.0000648

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460336 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726424

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.16C>A (p.Q6K) alteration is located in exon 1 (coding exon 1) of the RGS9 gene. This alteration results from a C to A substitution at nucleotide position 16, causing the glutamine (Q) at amino acid position 6 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RGS9-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 6 of the RGS9 protein (p.Gln6Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.24	.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.95, 0.93	.;P;P
Vest4		0.41
MutPred		0.26		Gain of methylation at Q6 (P = 0.0138);Gain of methylation at Q6 (P = 0.0138);Gain of methylation at Q6 (P = 0.0138);
MVP		0.55
MPC		0.24
ClinPred		0.27	T
GERP RS		4.0
Varity_R		0.33
gMVP		0.59

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: rs776631498; hg19: chr17-63133674;