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GeneBe

16-66924958-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 14/20 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

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.249
Variant links:
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]

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ACMG classification

Classification made for transcript

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 UniProt
RRADNM_004165.3 linkuse as main transcriptc.222G>C p.Glu74Asp missense_variant 2/5 ENST00000299759.11
RRADNM_001128850.2 linkuse as main transcriptc.222G>C p.Glu74Asp missense_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RRADENST00000299759.11 linkuse as main transcriptc.222G>C p.Glu74Asp missense_variant 2/51 NM_004165.3 P1
RRADENST00000568915.5 linkuse as main transcriptc.18G>C p.Glu6Asp missense_variant 1/35
RRADENST00000566577.1 linkuse as main transcript upstream_gene_variant 5

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 17, 2023The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1367652753; hg19: chr16-66958861; API