18-43115500-G-C

Variant names:

• chr18-43115500-G-C
• rs1381154303
• NM_002930.4:c.20C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002930.4(RIT2):​c.20C>G​(p.Ala7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RIT2 NM_002930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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]

ENSG00000287209 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08524451).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT2	NM_002930.4	c.20C>G	p.Ala7Gly	missense_variant	Exon 1 of 5	ENST00000326695.10	NP_002921.1
RIT2	NM_001272077.2	c.20C>G	p.Ala7Gly	missense_variant	Exon 1 of 6		NP_001259006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT2	ENST00000326695.10	c.20C>G	p.Ala7Gly	missense_variant	Exon 1 of 5	1	NM_002930.4	ENSP00000321805.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249102 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134652

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460700 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>G (p.A7G) alteration is located in exon 1 (coding exon 1) of the RIT2 gene. This alteration results from a C to G substitution at nucleotide position 20, causing the alanine (A) at amino acid position 7 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N;N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N;.;.
REVEL	Benign	0.042
Sift	Benign	0.26	T;.;.
Sift4G	Benign	0.43	T;T;D
Polyphen		0.079	B;B;.
Vest4		0.19
MutPred		0.15		Loss of stability (P = 0.0236);Loss of stability (P = 0.0236);Loss of stability (P = 0.0236);
MVP		0.82
MPC		0.48
ClinPred		0.25	T
GERP RS		4.5
Varity_R		0.070
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1381154303; hg19: chr18-40695465;