18-42743638-A-G

Position:

• chr18-42743638-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002930.4(RIT2):​c.509T>C​(p.Ile170Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RIT2 NM_002930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT2	NM_002930.4	c.509T>C	p.Ile170Thr	missense_variant	5/5	ENST00000326695.10	NP_002921.1
RIT2	NM_001272077.2	c.*111T>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.509T>C	p.Ile170Thr	missense_variant	5/5	1	NM_002930.4	ENSP00000321805	P1
RIT2	ENST00000589109.5	c.*111T>C		3_prime_UTR_variant	6/6	1		ENSP00000467217
RIT2	ENST00000590910.1	c.*61T>C		3_prime_UTR_variant	6/6	5		ENSP00000466620

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 03, 2023

The c.509T>C (p.I170T) alteration is located in exon 5 (coding exon 5) of the RIT2 gene. This alteration results from a T to C substitution at nucleotide position 509, causing the isoleucine (I) at amino acid position 170 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	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.69	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.38	B
Vest4		0.87
MutPred		0.82		Loss of stability (P = 0.0152);
MVP		0.87
MPC		1.0
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.60

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: rs939233556; hg19: chr18-40323603;