Genetic Variant MYCN:c.-101C>A (chr2-15941964-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_001293233.2(MYCN):c.174C>A(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,322,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A58A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

MYCN
NM_001293233.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.310

Publications

0 publications found

Variant links:

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 links:

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]

MYCNOS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP7

Synonymous conserved (PhyloP=-0.31 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293233.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYCN	NM_005378.6	MANE Select	c.-101C>A		5_prime_UTR	Exon 2 of 3	NP_005369.2
MYCN	NM_001293233.2		c.174C>A	p.Ala58Ala	synonymous	Exon 2 of 3	NP_001280162.1	Q9H224
MYCN	NM_001293228.2		c.-101C>A		5_prime_UTR	Exon 2 of 3	NP_001280157.1	P04198

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-101C>A	5_prime_UTR	Exon 2 of 3	ENSP00000281043.3	P04198
MYCN	ENST00000885101.1		c.-101C>A	5_prime_UTR	Exon 4 of 5	ENSP00000555160.1
MYCN	ENST00000930195.1		c.-101C>A	5_prime_UTR	Exon 2 of 3	ENSP00000600254.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.56e-7

AC:

AN:

1322828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

656606

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30380

American (AMR)

AF:

0.00

AC:

AN:

36258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23744

East Asian (EAS)

AF:

0.00

AC:

AN:

35890

South Asian (SAS)

AF:

0.00

AC:

AN:

76742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5310

European-Non Finnish (NFE)

AF:

9.88e-7

AC:

AN:

1012006

Other (OTH)

AF:

0.00

AC:

AN:

55616

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-0.31

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over