rs1284866728

Variant names:

• chr2-15940683-C-A
• rs1284866728
• NM_005378.6:c.-178C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-15940683-C-A
• chr2-15940683-C-G
• chr2-15940683-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001293231.2(MYCN):​c.97C>A​(p.Pro33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYCN NM_001293231.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.833
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14092073).

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.-178C>A		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.97C>A	p.Pro33Thr	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.97C>A	p.Pro33Thr	missense	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.-178C>A		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+291G>T		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.97C>A	p.Pro33Thr	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000161 AC: 4 AN: 247732 Hom.: 0 Cov.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 125462

African (AFR) AF: 0.00 AC: 0 AN: 7234

American (AMR) AF: 0.00 AC: 0 AN: 7438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9236

East Asian (EAS) AF: 0.00 AC: 0 AN: 22890

South Asian (SAS) AF: 0.00 AC: 0 AN: 3088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2310

European-Non Finnish (NFE) AF: 0.0000253 AC: 4 AN: 158228

Other (OTH) AF: 0.00 AC: 0 AN: 16484

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	MYCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.94
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.14	T
PhyloP100		0.83
GERP RS		3.0
PromoterAI		-0.024	Neutral
Mutation Taster		=297/3	polymorphism

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: rs1284866728; hg19: chr2-16080805;