2-15940647-G-T

Position:

• chr2-15940647-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005378.6(MYCN):​c.-214G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 400,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: MYCN NM_005378.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.40

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032213688).
• BP6: Variant 2-15940647-G-T is Benign according to our data. Variant chr2-15940647-G-T is described in ClinVar as [Benign]. Clinvar id is 2650691.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-15940647-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/152250) while in subpopulation NFE AF= 0.00246 (167/68000). AF 95% confidence interval is 0.00215. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 224 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYCN	NM_005378.6	c.-214G>T		5_prime_UTR_variant	1/3	ENST00000281043.4	NP_005369.2
MYCNOS	NR_110230.2	n.278+327C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYCN	ENST00000281043.4	c.-214G>T		5_prime_UTR_variant	1/3	5	NM_005378.6	ENSP00000281043	P1
MYCNOS	ENST00000641950.2	n.275+327C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00246

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00172 AC: 426 AN: 248106 Hom.: 0 Cov.: 0 AF XY: 0.00185 AC XY: 232 AN XY: 125670

Gnomad4 AFR exome AF: 0.000276

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000974

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.000432

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74438

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.00150

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

MYCN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2021

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

MYCN: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.95
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.032	T
MutationTaster	Benign	1.0	D
GERP RS		2.0

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: rs569527205; hg19: chr2-16080769;