4-150583180-CGC-GGA

Variant names:

• chr4-150583180-CGC-GGA
• NM_006439.5:c.151_153delCGCinsGGA
• MAB21L2 p.Arg51Gly

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Very_Strong PM5 PP3

The NM_006439.5(MAB21L2):​c.151_153delCGCinsGGA​(p.Arg51Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAB21L2 NM_006439.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97
• Publications: 0 publications found

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]

LRBA Gene-Disease associations (from GenCC):

• combined immunodeficiency due to LRBA deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_006439.5 (MAB21L2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-150583180-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 139621.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAB21L2	NM_006439.5	MANE Select	c.151_153delCGCinsGGA	p.Arg51Gly	missense	N/A	NP_006430.1	Q9Y586
	LRBA	NM_001364905.1	MANE Select	c.6330+4866_6330+4868delGCGinsTCC		intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.6363+4866_6363+4868delGCGinsTCC		intron	N/A	NP_001427359.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAB21L2	ENST00000317605.6	TSL:6 MANE Select	c.151_153delCGCinsGGA	p.Arg51Gly	missense	N/A	ENSP00000324701.4	Q9Y586
	LRBA	ENST00000651943.2	MANE Select	c.6330+4866_6330+4868delGCGinsTCC		intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.6363+4866_6363+4868delGCGinsTCC		intron	N/A	ENSP00000349629.3	P50851-1

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-151504332;