22-50777976-A-G

Position:

• chr22-50777976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001130919.3(RABL2B):​c.113T>C​(p.Met38Thr) 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: 29)
• Consequence: RABL2B NM_001130919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

Genes affected

RABL2B (HGNC:9800): (RAB, member of RAS oncogene family like 2B) The RABL2B protein is a member of the RAB gene family which belongs to the RAS GTPase superfamily. RABL2B is located within a subtelomeric region of 22q13.3. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

RPL23AP7 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABL2B	NM_001130919.3	c.113T>C	p.Met38Thr	missense_variant	3/9	ENST00000691320.1
RPL23AP82	NR_026981.1	n.242-5144A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABL2B	ENST00000691320.1	c.113T>C	p.Met38Thr	missense_variant	3/9		NM_001130919.3	A2
RPL23AP7	ENST00000496652.5	n.380-5144A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Aug 03, 2022

The c.113T>C (p.M38T) alteration is located in exon 4 (coding exon 2) of the RABL2B gene. This alteration results from a T to C substitution at nucleotide position 113, causing the methionine (M) at amino acid position 38 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	0.73
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.;T;T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.099
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;D;.;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.53	N;N;N;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		0.39	B;B;P;B;.;B;.
Vest4		0.81
MutPred		0.61		Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);Gain of phosphorylation at M38 (P = 0.0626);
MVP		0.75
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.44
gMVP		0.66

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: rs781969512; hg19: chr22-51216404;