2-15945879-C-T

Position:

• chr2-15945879-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005378.6(MYCN):​c.1177C>T​(p.Arg393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYCN NM_005378.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-15945880-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-15945879-C-T is Pathogenic according to our data. Variant chr2-15945879-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-15945879-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYCN	NM_005378.6	c.1177C>T	p.Arg393Cys	missense_variant	3/3	ENST00000281043.4	NP_005369.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043.4	c.1177C>T	p.Arg393Cys	missense_variant	3/3	5	NM_005378.6	ENSP00000281043.3
MYCN	ENST00000638417.1	c.544C>T	p.Arg182Cys	missense_variant	2/2	2		ENSP00000491476.1
MYCN	ENST00000703162.1	n.526C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2024	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: 15821734, 18470948, 35620261, 21224895) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 05, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg393 amino acid residue in MYCN. Other variant(s) that disrupt this residue have been observed in individuals with MYCN-related conditions (PMID: 15821734, 21224895), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYCN protein function. ClinVar contains an entry for this variant (Variation ID: 985302). This missense change has been observed in individual(s) with Feingold syndrome and/or MYCN-related conditions (PMID: 21224895; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the MYCN protein (p.Arg393Cys). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1177C>T (p.R393C) alteration is located in exon 3 (coding exon 2) of the MYCN gene. This alteration results from a C to T substitution at nucleotide position 1177, causing the arginine (R) at amino acid position 393 to be replaced by a cysteine (C). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the MYCN c.1177C>T alteration was not observed, with coverage at this position. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been described in a patient with features of Feingold syndrome including microcephaly, intellectual disability, digital abnormalities, growth retardation, micrognathia, and esophageal atresia (Cognet, 2011). In addition, other substitutions at the same codon have been reported in multiple affected individuals with Feingold syndrome, including p.R393S and p.R393H (Cognet, 2011; Marcelis, 2008; van Bokhoven, 2005). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R393 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.R393C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.91		Loss of MoRF binding (P = 0.0498);.;
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.99

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

Other links and lift over

dbSNP: rs104893647; hg19: chr2-16086001; COSMIC: COSV55258461; COSMIC: COSV55258461;