2-15942129-A-ACTCG

Position:

• chr2-15942129-A-ACTCG

Variant summary

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

The NM_005378.6(MYCN):​c.68_71dup​(p.Gln25AlafsTer11) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYCN NM_005378.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.63

Genes affected

MYCN (HGNC:7559): (MYCN proto-oncogene, bHLH transcription factor) This gene is a member of the MYC family and encodes a protein with a basic helix-loop-helix (bHLH) domain. This protein is located in the nucleus and must dimerize with another bHLH protein in order to bind DNA. Amplification of this gene is associated with a variety of tumors, most notably neuroblastomas. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

MYCNOS (HGNC:16911): (MYCN opposite strand) This gene is transcribed in antisense to the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene (MYCN). It is thought to encode a small, novel protein that stabilizes MYCN, prevents apoptosis, and promotes cell proliferation. Transcripts at this locus may also act directly as functional RNAs to recruit transcriptional regulators to the promoter of MYCN and stimulate transcription of this oncogene. This gene therefore functions through both RNA and protein products. [provided by RefSeq, Aug 2016]

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-15942129-A-ACTCG is Pathogenic according to our data. Variant chr2-15942129-A-ACTCG is described in ClinVar as [Pathogenic]. Clinvar id is 433150.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYCN	NM_005378.6	c.68_71dup	p.Gln25AlafsTer11	frameshift_variant	2/3	ENST00000281043.4	NP_005369.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043.4	c.68_71dup	p.Gln25AlafsTer11	frameshift_variant	2/3	5	NM_005378.6	ENSP00000281043	P1
MYCN	ENST00000638417.1	c.157+1389_157+1392dup		intron_variant		2		ENSP00000491476
MYCNOS	ENST00000641534.1	n.98+22_98+23insCGAG		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Feingold syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Jan 12, 2016

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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: rs1553370260; hg19: chr2-16082251;