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GeneBe

18-43115471-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002930.4(RIT2):c.49G>A(p.Gly17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,696 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: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RIT2
NM_002930.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
Variant links:
Genes affected
RIT2 (HGNC:10017): (Ras like without CAAX 2) RIN belongs to the RAS (HRAS; MIM 190020) superfamily of small GTPases (Shao et al., 1999 [PubMed 10545207]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.111414135).
BS2
High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIT2NM_002930.4 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant 1/5 ENST00000326695.10
RIT2NM_001272077.2 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant 1/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIT2ENST00000326695.10 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant 1/51 NM_002930.4 P1Q99578-1
RIT2ENST00000589109.5 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant 1/61 Q99578-2
RIT2ENST00000590910.1 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant 1/65
RIT2ENST00000650392.1 linkuse as main transcriptc.49G>A p.Gly17Arg missense_variant, NMD_transcript_variant 1/7

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250564
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135478
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461376
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
727010
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000380
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 GeneticsFeb 01, 2023The c.49G>A (p.G17R) alteration is located in exon 1 (coding exon 1) of the RIT2 gene. This alteration results from a G to A substitution at nucleotide position 49, causing the glycine (G) at amino acid position 17 to be replaced by an arginine (R). 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
0.29
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Uncertain
23
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.;T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.20
N;N;.
MutationTaster
Benign
0.95
D;D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.6
D;.;.
REVEL
Uncertain
0.31
Sift
Benign
0.27
T;.;.
Sift4G
Benign
0.13
T;T;D
Polyphen
0.072
B;B;.
Vest4
0.43
MutPred
0.35
Gain of solvent accessibility (P = 0.0042);Gain of solvent accessibility (P = 0.0042);Gain of solvent accessibility (P = 0.0042);
MVP
0.79
MPC
1.5
ClinPred
0.16
T
GERP RS
3.6
Varity_R
0.22
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs199603585; hg19: chr18-40695436; COSMIC: COSV104611832; API