rs188129461

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001293231.2(MYCN):​c.98C>A​(p.Pro33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 247,722 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: MYCN NM_001293231.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12257737).

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>A		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.98C>A	p.Pro33His	missense	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.98C>A	p.Pro33His	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>A		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+290G>T		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.98C>A	p.Pro33His	missense	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000807 AC: 2 AN: 247722 Hom.: 0 Cov.: 0 AF XY: 0.00000797 AC XY: 1 AN XY: 125460

African (AFR) AF: 0.00 AC: 0 AN: 7234

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 3090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2310

European-Non Finnish (NFE) AF: 0.0000126 AC: 2 AN: 158218

Other (OTH) AF: 0.00 AC: 0 AN: 16484

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.93
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.12	T
PhyloP100		-0.060
GERP RS		-1.8
PromoterAI		0.00080	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;