2-120285925-G-T

Position:

• chr2-120285925-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002881.3(RALB):​c.166G>T​(p.Val56Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RALB NM_002881.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

RALB (HGNC:9840): (RAS like proto-oncogene B) This gene encodes a GTP-binding protein that belongs to the small GTPase superfamily and Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALB	NM_002881.3	c.166G>T	p.Val56Phe	missense_variant	3/5	ENST00000272519.10	NP_002872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALB	ENST00000272519.10	c.166G>T	p.Val56Phe	missense_variant	3/5	1	NM_002881.3	ENSP00000272519.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 27, 2024

The c.166G>T (p.V56F) alteration is located in exon 3 (coding exon 2) of the RALB gene. This alteration results from a G to T substitution at nucleotide position 166, causing the valine (V) at amino acid position 56 to be replaced by a phenylalanine (F). 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	0.27
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D;D;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.6	.;L;L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.013	D;D;D;D;D
Sift4G	Benign	0.099	T;D;D;T;T
Polyphen		0.68	.;P;P;.;.
Vest4		0.79, 0.81
MutPred		0.48		.;Gain of ubiquitination at K53 (P = 0.0756);Gain of ubiquitination at K53 (P = 0.0756);Gain of ubiquitination at K53 (P = 0.0756);Gain of ubiquitination at K53 (P = 0.0756);
MVP		0.92
MPC		1.3
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.83

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: rs1690122539; hg19: chr2-121043501;