2-113628632-G-A

Variant names:

• chr2-113628632-G-A
• rs376664304
• NM_001306158.2:c.26G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001354425.2(RABL2A):​c.-253G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RABL2A NM_001354425.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0680

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066202104).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABL2A	NM_001306158.2	c.26G>A	p.Ser9Asn	missense_variant	Exon 2 of 9	ENST00000683472.1	NP_001293087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABL2A	ENST00000683472.1	c.26G>A	p.Ser9Asn	missense_variant	Exon 2 of 9		NM_001306158.2	ENSP00000507832.1

Frequencies

GnomAD3 genomes AF: 0.0000364 AC: 5 AN: 137380 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000147

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000714 AC: 10 AN: 1399692 Hom.: 0 Cov.: 25 AF XY: 0.00000577 AC XY: 4 AN XY: 692784

Gnomad4 AFR exome AF: 0.000247

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: 9.34e-7

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000364 AC: 5 AN: 137380 Hom.: 0 Cov.: 18 AF XY: 0.0000302 AC XY: 2 AN XY: 66272

Gnomad4 AFR AF: 0.000147

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: 0.00

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26G>A (p.S9N) alteration is located in exon 2 (coding exon 1) of the RABL2A gene. This alteration results from a G to A substitution at nucleotide position 26, causing the serine (S) at amino acid position 9 to be replaced by an asparagine (N). 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	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.80
DEOGEN2	Benign	0.083	T;.;.;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.78	.;.;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.;L;L;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.95	N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.42	T;T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T;T
Polyphen		0.011	B;B;.;.;B;.;B
Vest4		0.20
MVP		0.58
MPC		1.5
ClinPred		0.024	T
GERP RS		-1.4
Varity_R		0.036
gMVP		0.22

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

Other links and lift over

dbSNP: rs376664304; hg19: chr2-114386209;