2-113640946-C-A

Variant names:

• chr2-113640946-C-A
• NM_001306158.2:c.350C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001306158.2(RABL2A):​c.350C>A​(p.Thr117Lys) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RABL2A NM_001306158.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

RABL2A (HGNC:9799): (RAB, member of RAS oncogene family like 2A) This gene is a member of the RAB gene family which belongs to the RAS GTPase superfamily. The proteins in the family of RAS-related signaling molecules are small GTP-binding proteins that play important roles in the regulation of exocytotic and endocytotic pathways. This gene maps to the site of an ancestral telomere fusion event and may be a subtelomeric gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0390957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABL2A	NM_001306158.2	c.350C>A	p.Thr117Lys	missense_variant	Exon 6 of 9	ENST00000683472.1	NP_001293087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABL2A	ENST00000683472.1	c.350C>A	p.Thr117Lys	missense_variant	Exon 6 of 9		NM_001306158.2	ENSP00000507832.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000342 AC: 5 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.350C>A (p.T117K) alteration is located in exon 6 (coding exon 5) of the RABL2A gene. This alteration results from a C to A substitution at nucleotide position 350, causing the threonine (T) at amino acid position 117 to be replaced by a lysine (K). 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	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.0
DANN	Benign	0.14
DEOGEN2	Benign	0.059	T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.3	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.6	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.23
MutPred		0.43		Gain of ubiquitination at T117 (P = 0.023);Gain of ubiquitination at T117 (P = 0.023);Gain of ubiquitination at T117 (P = 0.023);Gain of ubiquitination at T117 (P = 0.023);
MVP		0.30
MPC		1.9
ClinPred		0.028	T
GERP RS		1.0
Varity_R		0.029
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr2-114398523;