4-150583314-CGGCTGCGCA-C

Variant names:

• chr4-150583314-CGGCTGCGCA-C
• rs1771647082
• NM_006439.5:c.287_295delGCTGCGCAG

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_006439.5(MAB21L2):​c.287_295delGCTGCGCAG​(p.Gly96_Ala98del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAB21L2 NM_006439.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 10.0

Genes affected

MAB21L2 (HGNC:6758): (mab-21 like 2) This gene is similar to the C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. The protein encoded by this gene is primarily nuclear, although some cytoplasmic localization has been observed. [provided by RefSeq, Jul 2008]

LRBA (HGNC:1742): (LPS responsive beige-like anchor protein) The protein encoded by this gene is a member of the WDL-BEACH-WD (WBW) gene family. Its expression is induced in B cells and macrophages by bacterial lipopolysaccharides (LPS). The encoded protein associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in the secretion and/or membrane deposition of immune effector molecules. Defects in this gene are associated with the disorder common variable immunodeficiency-8 with autoimmunity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006439.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAB21L2	NM_006439.5	c.287_295delGCTGCGCAG	p.Gly96_Ala98del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000317605.6	NP_006430.1
LRBA	NM_001364905.1	c.6330+4725_6330+4733delTGCGCAGCC		intron_variant	Intron 40 of 56	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAB21L2	ENST00000317605.6	c.287_295delGCTGCGCAG	p.Gly96_Ala98del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_006439.5	ENSP00000324701.4
LRBA	ENST00000651943.2	c.6330+4725_6330+4733delTGCGCAGCC		intron_variant	Intron 40 of 56		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Colobomatous microphthalmia-rhizomelic dysplasia syndrome Uncertain:1

Feb 08, 2019

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gly96_Ala98del variant in the MAB21L2 gene was identified de novo in this individual, but has not been previously reported in association with disease. The p.Gly96_Ala98del variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). However, the ability to detect large insertion/deletion variants is limited. The p.Gly96_Ala98del variant results in an inframe deletion of 3 amino acids. The significance of this type of variation in the MAB21L2 gene is currently unclear, as previously reported disease-causing variants in MAB21L2 have been missense or truncating variants. This individual was also identified with a pathogenic variant in the SOX2 gene, which is consistent with their clinical findings. This reduces but does not eliminate the likelihood of this variant contributing to this patient’s features. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly96_Ala98del variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PS2_supporting, PM2, BP5] -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1771647082; hg19: chr4-151504466;