2-15940678-G-C

Variant names:

• chr2-15940678-G-C
• rs1241796486
• NM_005378.6:c.-183G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001293231.2(MYCN):​c.92G>C​(p.Arg31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.074 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYCN NM_001293231.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15255892).

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.-183G>C		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.92G>C	p.Arg31Pro	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.92G>C	p.Arg31Pro	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.-183G>C		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+296C>G		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.92G>C	p.Arg31Pro	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 560 AN: 145068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00293

Gnomad AMI AF: 0.00568

Gnomad AMR AF: 0.00395

Gnomad ASJ AF: 0.000596

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00799

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0740 AC: 4803 AN: 64912 Hom.: 0 Cov.: 0 AF XY: 0.0753 AC XY: 2476 AN XY: 32886

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0759 AC: 142 AN: 1872

American (AMR) AF: 0.0812 AC: 166 AN: 2044

Ashkenazi Jewish (ASJ) AF: 0.0728 AC: 170 AN: 2334

East Asian (EAS) AF: 0.0564 AC: 338 AN: 5988

South Asian (SAS) AF: 0.0630 AC: 59 AN: 936

European-Finnish (FIN) AF: 0.0991 AC: 504 AN: 5086

Middle Eastern (MID) AF: 0.0138 AC: 19 AN: 1372

European-Non Finnish (NFE) AF: 0.0751 AC: 3069 AN: 40858

Other (OTH) AF: 0.0760 AC: 336 AN: 4422

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00380 AC: 552 AN: 145204 Hom.: 0 Cov.: 32 AF XY: 0.00383 AC XY: 271 AN XY: 70690

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00287 AC: 116 AN: 40352

American (AMR) AF: 0.00394 AC: 58 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 2 AN: 3358

East Asian (EAS) AF: 0.0224 AC: 99 AN: 4420

South Asian (SAS) AF: 0.0204 AC: 86 AN: 4226

European-Finnish (FIN) AF: 0.00799 AC: 75 AN: 9390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00168 AC: 110 AN: 65530

Other (OTH) AF: 0.000487 AC: 1 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.87
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.15	T
PhyloP100		0.21
GERP RS		1.2
PromoterAI		0.047	Neutral
Mutation Taster		=300/0	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: rs1241796486; hg19: chr2-16080800;