NM_005378.6:c.-183G>A

Variant names:

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

Variant summary

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

The NM_005378.6(MYCN):​c.-183G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 256,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MYCN NM_005378.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.14026946).

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.-183G>A		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.92G>A	p.Arg31His	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.92G>A	p.Arg31His	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>A		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+296C>T		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.92G>A	p.Arg31His	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146320 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000217

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 4 AN: 110058 Hom.: 0 Cov.: 0 AF XY: 0.0000359 AC XY: 2 AN XY: 55678

African (AFR) AF: 0.00 AC: 0 AN: 3324

American (AMR) AF: 0.00 AC: 0 AN: 3542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4154

East Asian (EAS) AF: 0.00 AC: 0 AN: 9864

South Asian (SAS) AF: 0.00 AC: 0 AN: 1696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1612

European-Non Finnish (NFE) AF: 0.0000576 AC: 4 AN: 69438

Other (OTH) AF: 0.00 AC: 0 AN: 7546

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146320 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71150

African (AFR) AF: 0.00 AC: 0 AN: 40494

American (AMR) AF: 0.00 AC: 0 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.000217 AC: 1 AN: 4614

South Asian (SAS) AF: 0.00 AC: 0 AN: 4374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65862

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Feingold syndrome type 1;C5935591:Megalencephaly-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.97
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.14	T
PhyloP100		0.21
GERP RS		1.2
PromoterAI		0.014	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;