16-66924958-C-G

Position:

• chr16-66924958-C-G

Variant summary

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

The NM_004165.3(RRAD):​c.222G>C​(p.Glu74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RRAD NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.249

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]

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=0.096101165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAD	NM_004165.3	c.222G>C	p.Glu74Asp	missense_variant	2/5	ENST00000299759.11	NP_004156.1
RRAD	NM_001128850.2	c.222G>C	p.Glu74Asp	missense_variant	2/5		NP_001122322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRAD	ENST00000299759.11	c.222G>C	p.Glu74Asp	missense_variant	2/5	1	NM_004165.3	ENSP00000299759	P1
RRAD	ENST00000568915.5	c.18G>C	p.Glu6Asp	missense_variant	1/3	5		ENSP00000461995
RRAD	ENST00000566577.1			upstream_gene_variant		5		ENSP00000462559

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The c.222G>C (p.E74D) alteration is located in exon 2 (coding exon 1) of the RRAD gene. This alteration results from a G to C substitution at nucleotide position 222, causing the glutamic acid (E) at amino acid position 74 to be replaced by an aspartic acid (D). 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	0.082
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.046
Sift	Benign	0.33	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.083	B;B
Vest4		0.13
MutPred		0.12		Loss of glycosylation at S76 (P = 0.1867);Loss of glycosylation at S76 (P = 0.1867);
MVP		0.70
MPC		0.61
ClinPred		0.19	T
GERP RS		2.2
Varity_R		0.070
gMVP		0.35

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: rs1367652753; hg19: chr16-66958861;