dbSNP rs569527205: MYCN:c.-214G>T (chr2-15940647-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001293231.2(MYCN):c.61G>T(p.Ala21Ser) variant causes a missense 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. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 0 hom. )

Consequence

MYCN
NM_001293231.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.40

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2650691.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 224 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293231.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYCN	NM_005378.6	MANE Select	c.-214G>T		5_prime_UTR	Exon 1 of 3	NP_005369.2
MYCN	NM_001293231.2		c.61G>T	p.Ala21Ser	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
MYCN	NM_001293233.2		c.61G>T	p.Ala21Ser	missense	Exon 1 of 3	NP_001280162.1	Q9H224

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-214G>T		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
MYCNOS	ENST00000419083.7	TSL:1	n.347-296C>A		intron	N/A
MYCN	ENST00000638417.1	TSL:2	c.61G>T	p.Ala21Ser	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152134

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00185

AC XY:

232

AN XY:

125670

show subpopulations

African (AFR)

AF:

0.000276

AC:

AN:

7240

American (AMR)

AF:

0.00134

AC:

AN:

7442

Ashkenazi Jewish (ASJ)

AF:

0.000974

AC:

AN:

9240

East Asian (EAS)

AF:

0.00

AC:

AN:

22892

South Asian (SAS)

AF:

0.00161

AC:

AN:

3108

European-Finnish (FIN)

AF:

0.000432

AC:

AN:

20824

Middle Eastern (MID)

AF:

0.000769

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.00231

AC:

365

AN:

158242

Other (OTH)

AF:

0.00145

AC:

AN:

16516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00147

AC:

224

AN:

152250

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41570

American (AMR)

AF:

0.000915

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000775

AC:

AN:

5160

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00246

AC:

167

AN:

68000

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Feingold syndrome type 1;C5935591:Megalencephaly-polydactyly syndrome (1)

MYCN-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.95

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.44

MetaRNN

Benign

0.032

PhyloP100

1.4

GERP RS

2.0

PromoterAI

-0.10

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over