2-15941981-G-T

Variant names:

• chr2-15941981-G-T
• rs981068491
• NM_005378.6:c.-84G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001293233.2(MYCN):​c.191G>T​(p.Arg64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,401,406 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (1 hom.)
• Consequence: MYCN NM_001293233.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0430

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYCN	NM_005378.6	c.-84G>T		5_prime_UTR_variant	Exon 2 of 3	ENST00000281043.4	NP_005369.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043	c.-84G>T		5_prime_UTR_variant	Exon 2 of 3	5	NM_005378.6	ENSP00000281043.3
MYCN	ENST00000638417.1	c.157+1238G>T		intron_variant	Intron 1 of 1	2		ENSP00000491476.1
MYCNOS	ENST00000641534.1	n.98+171C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401406 Hom.: 1 Cov.: 27 AF XY: 0.00000288 AC XY: 2 AN XY: 694988

Gnomad4 AFR exome AF: 0.0000312

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Feingold syndrome type 1 Uncertain:1

Jul 02, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. A single variant has been reported with gain of function properties (p.Thr58Met), as it results in protection from phosphorylation and consequently protein degradation (PMID: 30573562). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a leucine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD v3. (P) 0502 - Missense variant with uninformative in silico predictions and/or conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs981068491; hg19: chr2-16082103;