chr2-15945762-G-GC

Variant names:

• chr2-15945762-G-GC
• rs1553370963
• NM_005378.6:c.1061dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005378.6(MYCN):​c.1061dupC​(p.Ser355ValfsTer14) 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 (★). Synonymous variant affecting the same amino acid position (i.e. A354A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYCN NM_005378.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.774
• 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]

MYCN Gene-Disease associations (from GenCC):

• Feingold syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-15945762-G-GC is Pathogenic according to our data. Variant chr2-15945762-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 433152.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005378.6. 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.1061dupC	p.Ser355ValfsTer14	frameshift	Exon 3 of 3	NP_005369.2
	MYCN	NM_001293228.2		c.1061dupC	p.Ser355ValfsTer14	frameshift	Exon 3 of 3	NP_001280157.1	P04198
	MYCN	NM_001293231.2		c.428dupC	p.Ser144ValfsTer14	frameshift	Exon 2 of 2	NP_001280160.1	A0A1W2PPD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.1061dupC	p.Ser355ValfsTer14	frameshift	Exon 3 of 3	ENSP00000281043.3	P04198
	MYCN	ENST00000885101.1		c.1061dupC	p.Ser355ValfsTer14	frameshift	Exon 5 of 5	ENSP00000555160.1
	MYCN	ENST00000930195.1		c.1061dupC	p.Ser355ValfsTer14	frameshift	Exon 3 of 3	ENSP00000600254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
Mutation Taster		=2/198	disease causing (ClinVar)

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

dbSNP: rs1553370963; hg19: chr2-16085884;