Genetic Variant MYCN:c.-117-126G>A (chr2-15941822-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005378.6(MYCN):c.-117-126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 595,640 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 39 hom., cov: 33)

Exomes 𝑓: 0.018 ( 164 hom. )

Consequence

MYCN
NM_005378.6 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0680

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-15941822-G-A is Benign according to our data. Variant chr2-15941822-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1191232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYCN	NM_005378.6 link	c.-117-126G>A		intron_variant	Intron 1 of 2	ENST00000281043.4	NP_005369.2	P04198

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043.4 link	c.-117-126G>A		intron_variant	Intron 1 of 2	5	NM_005378.6	ENSP00000281043.3		P04198

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2589

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0602

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0139

GnomAD4 exome

AF:

0.0182

AC:

8075

AN:

443360

Hom.:

164

Cov.:

AF XY:

0.0205

AC XY:

4789

AN XY:

233290

show subpopulations

Gnomad4 AFR exome

AF:

0.0194

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.000163

Gnomad4 SAS exome

AF:

0.0554

Gnomad4 FIN exome

AF:

0.00844

Gnomad4 NFE exome

AF:

0.0160

Gnomad4 OTH exome

AF:

0.0158

GnomAD4 genome

AF:

0.0170

AC:

2596

AN:

152280

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1314

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0185

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.00233

Gnomad4 SAS

AF:

0.0599

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0151

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.6

DANN

Benign

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over