2-15945883-G-T

Variant names:

• chr2-15945883-G-T
• rs104893648
• NM_005378.6:c.1181G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_005378.6(MYCN):​c.1181G>T​(p.Arg394Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R394C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYCN NM_005378.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.09
• Publications: 4 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 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005378.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-15945882-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1960211.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 2-15945883-G-T is Pathogenic according to our data. Variant chr2-15945883-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433153.

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.1181G>T	p.Arg394Leu	missense	Exon 3 of 3	NP_005369.2
	MYCN	NM_001293228.2		c.1181G>T	p.Arg394Leu	missense	Exon 3 of 3	NP_001280157.1	P04198
	MYCN	NM_001293231.2		c.548G>T	p.Arg183Leu	missense	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.1181G>T	p.Arg394Leu	missense	Exon 3 of 3	ENSP00000281043.3	P04198
	MYCN	ENST00000885101.1		c.1181G>T	p.Arg394Leu	missense	Exon 5 of 5	ENSP00000555160.1
	MYCN	ENST00000930195.1		c.1181G>T	p.Arg394Leu	missense	Exon 3 of 3	ENSP00000600254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Feingold syndrome type 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.82		Loss of MoRF binding (P = 0.0286)
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.99
Mutation Taster		=26/74	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: rs104893648; hg19: chr2-16086005;