rs758327096

Variant names:

• chr16-66925145-C-G
• rs758327096
• NM_004165.3:c.35G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004165.3(RRAD):​c.35G>C​(p.Gly12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,226,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: RRAD NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2204994).
• BS2: High AC in GnomAdExome4 at 28 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.35G>C	p.Gly12Ala	missense	Exon 2 of 5	NP_004156.1	P55042
	RRAD	NM_001128850.2		c.35G>C	p.Gly12Ala	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.35G>C	p.Gly12Ala	missense	Exon 2 of 5	ENSP00000299759.6	P55042
	RRAD	ENST00000889788.1		c.35G>C	p.Gly12Ala	missense	Exon 1 of 4	ENSP00000559848.1
	RRAD	ENST00000889790.1		c.35G>C	p.Gly12Ala	missense	Exon 2 of 5	ENSP00000559849.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 2468 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 28 AN: 1074712 Hom.: 0 Cov.: 30 AF XY: 0.0000256 AC XY: 13 AN XY: 508074

African (AFR) AF: 0.0000883 AC: 2 AN: 22656

American (AMR) AF: 0.00 AC: 0 AN: 8292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13934

East Asian (EAS) AF: 0.00 AC: 0 AN: 26138

South Asian (SAS) AF: 0.00 AC: 0 AN: 19346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2880

European-Non Finnish (NFE) AF: 0.0000283 AC: 26 AN: 917252

Other (OTH) AF: 0.00 AC: 0 AN: 43146

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000126 AC: 1

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	0.079
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.50
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.17		Loss of loop (P = 0.1242)
MVP		0.72
MPC		1.5
ClinPred		0.40	T
GERP RS		3.4
PromoterAI		-0.037	Neutral
Varity_R		0.082
gMVP		0.33
Mutation Taster		=94/6	polymorphism

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: rs758327096; hg19: chr16-66959048;