2-15940646-CG-C

Variant names:

• chr2-15940646-CG-C
• NM_005378.6:c.-214delG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1 PM2 BP6

The NM_001293231.2(MYCN):​c.61delG​(p.Ala21HisfsTer4) 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 benign (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYCN NM_001293231.2 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 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 42 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-15940646-CG-C is Benign according to our data. Variant chr2-15940646-CG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3236331.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293231.2. 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
	MYCN	NM_005378.6	MANE Select	c.-214delG		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.61delG	p.Ala21HisfsTer4	frameshift	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.61delG	p.Ala21HisfsTer4	frameshift	Exon 1 of 3	NP_001280162.1	Q9H224

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-214delG		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.347-296delC		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.61delG	p.Ala21HisfsTer4	frameshift	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Feingold syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

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

Other links and lift over

hg19: chr2-16080768;