rs188129461

Variant names:

• chr2-15940684-C-T
• rs188129461
• NM_005378.6:c.-177C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-15940684-C-T
• chr2-15940684-C-A
• chr2-15940684-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001293231.2(MYCN):​c.98C>T​(p.Pro33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 152,278 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYCN NM_001293231.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.0600
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032662153).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00242 (369/152278) while in subpopulation SAS AF = 0.0292 (141/4830). AF 95% confidence interval is 0.0253. There are 2 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 369 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	NM_005378.6	MANE Select	c.-177C>T		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.98C>T	p.Pro33Leu	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.98C>T	p.Pro33Leu	missense	Exon 1 of 3	NP_001280162.1	Q9H224

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.-177C>T		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+290G>A		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.98C>T	p.Pro33Leu	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 369 AN: 152160 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00335

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00178 AC: 441 AN: 247722 Hom.: 2 Cov.: 0 AF XY: 0.00192 AC XY: 241 AN XY: 125462

African (AFR) AF: 0.000276 AC: 2 AN: 7234

American (AMR) AF: 0.00188 AC: 14 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9236

East Asian (EAS) AF: 0.00 AC: 0 AN: 22890

South Asian (SAS) AF: 0.0327 AC: 101 AN: 3090

European-Finnish (FIN) AF: 0.000144 AC: 3 AN: 20826

Middle Eastern (MID) AF: 0.00346 AC: 8 AN: 2310

European-Non Finnish (NFE) AF: 0.00185 AC: 292 AN: 158218

Other (OTH) AF: 0.00127 AC: 21 AN: 16484

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152278 Hom.: 2 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74460

African (AFR) AF: 0.000433 AC: 18 AN: 41586

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000583 Hom.: 0

Bravo AF: 0.00180

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Feingold syndrome type 1;C5935591:Megalencephaly-polydactyly syndrome (1)
-	-	1	MYCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.96
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0033	T
PhyloP100		-0.060
GERP RS		-1.8
PromoterAI		0.022	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs188129461; hg19: chr2-16080806;