Variant chr2-15945847-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_005378.6(MYCN):c.1145G>A(p.Arg382His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYCN
NM_005378.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.70

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain bHLH (size 52) in uniprot entity MYCN_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005378.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYCN	NM_005378.6 linkuse as main transcript	c.1145G>A	p.Arg382His	missense_variant	3/3	ENST00000281043.4	NP_005369.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYCN	ENST00000281043.4 linkuse as main transcript	c.1145G>A	p.Arg382His	missense_variant	3/3	5	NM_005378.6	ENSP00000281043	P1
MYCN	ENST00000638417.1 linkuse as main transcript	c.512G>A	p.Arg171His	missense_variant	2/2	2		ENSP00000491476
MYCN	ENST00000703162.1 linkuse as main transcript	n.494G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Feingold syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28423360, 26147798, 32925198, 18671284) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.5

D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.79

Loss of MoRF binding (P = 0.0491);.;

MVP

0.91

MPC

2.1

ClinPred

0.98

GERP RS

5.1

Varity_R

0.47

gMVP

0.87

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