Genetic Variant MYCN:c.-177C>T (chr2-15940684-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001293231.2(MYCN):c.98C>T(p.Pro33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 152,278 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

MYCN
NM_001293231.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0600

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032662153).

BP6

Variant 2-15940684-C-T is Benign according to our data. Variant chr2-15940684-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041890.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00242 (369/152278) while in subpopulation SAS AF= 0.0292 (141/4830). AF 95% confidence interval is 0.0253. There are 2 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYCN	NM_005378.6 link	c.-177C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000281043.4	NP_005369.2	P04198

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043 link	c.-177C>T		5_prime_UTR_variant	Exon 1 of 3	5	NM_005378.6	ENSP00000281043.3		P04198

Frequencies

GnomAD3 genomes

AF:

0.00243

AC:

369

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00335

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00178

AC:

441

AN:

247722

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

241

AN XY:

125462

show subpopulations

Gnomad4 AFR exome

AF:

0.000276

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0327

Gnomad4 FIN exome

AF:

0.000144

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.00242

AC:

369

AN:

152278

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.0292

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000583

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MYCN-related disorder

Benign:1

Jun 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.96

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0033

GERP RS

-1.8

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