22-27751055-CA-C

Position:

• chr22-27751055-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002430.3(MN1):​c.3822del​(p.Gly1275AlafsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MN1 NM_002430.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.27

Genes affected

MN1 (HGNC:7180): (MN1 proto-oncogene, transcriptional regulator) Meningioma 1 (MN1) contains two sets of CAG repeats. It is disrupted by a balanced translocation (4;22) in a meningioma, and its inactivation may contribute to meningioma 32 pathogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-27751055-CA-C is Pathogenic according to our data. Variant chr22-27751055-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2443066.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MN1	NM_002430.3	c.3822del	p.Gly1275AlafsTer45	frameshift_variant	2/2	ENST00000302326.5	NP_002421.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MN1	ENST00000302326.5	c.3822del	p.Gly1275AlafsTer45	frameshift_variant	2/2	1	NM_002430.3	ENSP00000304956	P1
MN1	ENST00000497225.1	n.178del		non_coding_transcript_exon_variant	2/2	1
MN1	ENST00000703102.1	n.347del		non_coding_transcript_exon_variant	2/2
MN1	ENST00000424656.1	c.175del	p.Gly60AlafsTer45	frameshift_variant, NMD_transcript_variant	2/3	5		ENSP00000397805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CEBALID syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Nov 03, 2022

This MN1 variant is absent from a large population dataset and has not been reported in ClinVar nor the literature, to our knowledge. This frameshift variant is predicted to lead to a premature termination signal within the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. This variant clusters with other reported MN1 truncating variants identified in individuals with MCTT syndrome. Parental specimens were unavailable to confirm that this variant is de novo. We consider c.3822delT (p.Gly1275fs) to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-28147043;