10-119527410-C-T

Variant names:

• chr10-119527410-C-T
• rs765617830
• NM_001005339.2:c.64G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001005339.2(RGS10):​c.64G>A​(p.Asp22Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RGS10 NM_001005339.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

RGS10 (HGNC:9992): (regulator of G protein signaling 10) Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 10 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. This protein associates specifically with the activated forms of the two related G-protein subunits, G-alphai3 and G-alphaz but fails to interact with the structurally and functionally distinct G-alpha subunits. Regulator of G protein signaling 10 protein is localized in the nucleus. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18344557).
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS10	NM_001005339.2	c.64G>A	p.Asp22Asn	missense_variant	Exon 2 of 5	ENST00000369103.3	NP_001005339.1
RGS10	NM_002925.4	c.22G>A	p.Asp8Asn	missense_variant	Exon 2 of 5		NP_002916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS10	ENST00000369103.3	c.64G>A	p.Asp22Asn	missense_variant	Exon 2 of 5	1	NM_001005339.2	ENSP00000358099.2
RGS10	ENST00000369101.7	c.40G>A	p.Asp14Asn	missense_variant	Exon 1 of 4	1		ENSP00000358097.3
RGS10	ENST00000392865.5	c.22G>A	p.Asp8Asn	missense_variant	Exon 2 of 5	1		ENSP00000376605.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251382 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64G>A (p.D22N) alteration is located in exon 2 (coding exon 2) of the RGS10 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the aspartic acid (D) at amino acid position 22 to be replaced by an asparagine (N). 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	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	.;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.68	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.33
MutPred		0.12		.;Loss of phosphorylation at S13 (P = 0.1384);.;
MVP		0.72
MPC		0.84
ClinPred		0.11	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765617830; hg19: chr10-121286922;