16-66924855-G-C

Variant names:

• chr16-66924855-G-C
• rs751752299
• NM_004165.3:c.325C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004165.3(RRAD):​c.325C>G​(p.Arg109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,435,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: RRAD NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

Genes affected

RRAD (HGNC:10446): (RRAD, Ras related glycolysis inhibitor and calcium channel regulator) Predicted to enable GTP binding activity and calcium channel regulator activity. Predicted to be involved in small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in plasma membrane. Implicated in type 2 diabetes mellitus. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

RRAD Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31252345).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004165.3. 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
	RRAD	NM_004165.3	MANE Select	c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	NP_004156.1	P55042
	RRAD	NM_001128850.2		c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	NP_001122322.1	P55042

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAD	ENST00000299759.11	TSL:1 MANE Select	c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	ENSP00000299759.6	P55042
	RRAD	ENST00000889788.1		c.325C>G	p.Arg109Gly	missense	Exon 1 of 4	ENSP00000559848.1
	RRAD	ENST00000889790.1		c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	ENSP00000559849.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000174 AC: 4 AN: 229518 AF XY: 0.00000789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1435390 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715008

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 44062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39102

South Asian (SAS) AF: 0.00 AC: 0 AN: 84922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103648

Other (OTH) AF: 0.00 AC: 0 AN: 59572

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.22	N
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.52
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.65	P
Vest4		0.51
MutPred		0.51		Loss of stability (P = 0.0098)
MVP		0.85
MPC		1.4
ClinPred		0.35	T
GERP RS		4.1
PromoterAI		0.063	Neutral
Varity_R		0.51
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751752299; hg19: chr16-66958758;