18-42743569-T-G

Position:

• chr18-42743569-T-G

Variant summary

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

The NM_002930.4(RIT2):​c.578A>C​(p.Lys193Thr) 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. 14/21 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)
• Consequence: RIT2 NM_002930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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]

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=0.16768628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT2	NM_002930.4	c.578A>C	p.Lys193Thr	missense_variant	5/5	ENST00000326695.10	NP_002921.1
RIT2	NM_001272077.2	c.*180A>C		3_prime_UTR_variant	6/6		NP_001259006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT2	ENST00000326695.10	c.578A>C	p.Lys193Thr	missense_variant	5/5	1	NM_002930.4	ENSP00000321805.4
RIT2	ENST00000589109.5	c.*180A>C		3_prime_UTR_variant	6/6	1		ENSP00000467217.1
RIT2	ENST00000590910.1	c.*130A>C		3_prime_UTR_variant	6/6	5		ENSP00000466620.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Feb 16, 2023

The c.578A>C (p.K193T) alteration is located in exon 5 (coding exon 5) of the RIT2 gene. This alteration results from a A to C substitution at nucleotide position 578, causing the lysine (K) at amino acid position 193 to be replaced by a threonine (T). 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	0.18
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.091	T
Polyphen		0.079	B
Vest4		0.25
MutPred		0.34		Loss of methylation at K193 (P = 0.0075);
MVP		0.79
MPC		0.57
ClinPred		0.22	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-40323534;