NM_005378.6:c.-133C>T

Variant names:

• chr2-15940728-C-T
• rs1024707963
• NM_005378.6:c.-133C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_005378.6(MYCN):​c.-133C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 399,304 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MYCN NM_005378.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.365
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-15940728-C-T is Benign according to our data. Variant chr2-15940728-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3030404.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 5 AD gene.

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.-133C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_005369.2
	MYCN	NM_005378.6	MANE Select	c.-133C>T		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293228.2		c.-443C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001280157.1	P04198

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-133C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-133C>T		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+246G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 7 AN: 247034 Hom.: 0 Cov.: 0 AF XY: 0.0000320 AC XY: 4 AN XY: 125150

African (AFR) AF: 0.00 AC: 0 AN: 7202

American (AMR) AF: 0.000134 AC: 1 AN: 7436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9230

East Asian (EAS) AF: 0.00 AC: 0 AN: 22892

South Asian (SAS) AF: 0.00 AC: 0 AN: 3066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20826

Middle Eastern (MID) AF: 0.000544 AC: 1 AN: 1838

European-Non Finnish (NFE) AF: 0.0000253 AC: 4 AN: 158120

Other (OTH) AF: 0.0000609 AC: 1 AN: 16424

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74440

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		0.36
PromoterAI		0.060	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: rs1024707963; hg19: chr2-16080850;