chr2-15942295-G-T

Variant names:

• chr2-15942295-G-T
• rs121913667
• NM_005378.6:c.231G>T

Variant summary

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

The NM_005378.6(MYCN):​c.231G>T​(p.Trp77Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYCN NM_005378.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.27
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005378.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	NM_005378.6	MANE Select	c.231G>T	p.Trp77Cys	missense	Exon 2 of 3	NP_005369.2
	MYCN	NM_001293228.2		c.231G>T	p.Trp77Cys	missense	Exon 2 of 3	NP_001280157.1
	MYCNOS	NR_161163.1		n.139C>A		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCN	ENST00000281043.4	TSL:5 MANE Select	c.231G>T	p.Trp77Cys	missense	Exon 2 of 3	ENSP00000281043.3
	MYCNOS	ENST00000641534.2		n.147C>A		non_coding_transcript_exon	Exon 1 of 3
	MYCNOS	ENST00000817587.1		n.139C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.21
Sift	Uncertain	0.017	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.46		Gain of helix (P = 0.0325)
MVP		0.14
MPC		2.3
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.74
gMVP		0.61
Mutation Taster		=10/90	disease causing

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: rs121913667; hg19: chr2-16082417;