22-50768810-G-A

Position:

• chr22-50768810-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130919.3(RABL2B):​c.656C>T​(p.Thr219Ile) 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. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RABL2B NM_001130919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.523

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0861271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABL2B	NM_001130919.3	c.656C>T	p.Thr219Ile	missense_variant	9/9	ENST00000691320.1
RPL23AP82	NR_026981.1	n.241+11484G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABL2B	ENST00000691320.1	c.656C>T	p.Thr219Ile	missense_variant	9/9		NM_001130919.3	A2
RPL23AP7	ENST00000496652.5	n.379+11484G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000164 AC: 24 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 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: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 27

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

Nov 09, 2023

The c.683C>T (p.T228I) alteration is located in exon 10 (coding exon 8) of the RABL2B gene. This alteration results from a C to T substitution at nucleotide position 683, causing the threonine (T) at amino acid position 228 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.1
DANN	Benign	0.96
DEOGEN2	Benign	0.014	T;.;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.71	T;.;T;.;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.086	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.018	D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;.;B
Vest4		0.24
MutPred		0.090		Loss of phosphorylation at T218 (P = 0.0111);.;.;Loss of phosphorylation at T218 (P = 0.0111);.;.;
MVP		0.30
ClinPred		0.056	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.38

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: rs2083716912; hg19: chr22-51207238;