2-15940691-A-C

Variant names:

• chr2-15940691-A-C
• rs1662614831
• NM_005378.6:c.-170A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001293231.2(MYCN):​c.105A>C​(p.Pro35Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYCN NM_001293231.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.495
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-15940691-A-C is Benign according to our data. Variant chr2-15940691-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2650692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.495 with no splicing effect.

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.-170A>C		5_prime_UTR	Exon 1 of 3	NP_005369.2
	MYCN	NM_001293231.2		c.105A>C	p.Pro35Pro	synonymous	Exon 1 of 2	NP_001280160.1	A0A1W2PPD9
	MYCN	NM_001293233.2		c.105A>C	p.Pro35Pro	synonymous	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.-170A>C		5_prime_UTR	Exon 1 of 3	ENSP00000281043.3	P04198
	MYCNOS	ENST00000419083.7	TSL:1	n.346+283T>G		intron	N/A
	MYCN	ENST00000638417.1	TSL:2	c.105A>C	p.Pro35Pro	synonymous	Exon 1 of 2	ENSP00000491476.1	A0A1W2PPD9

Frequencies

GnomAD3 genomes AF: 0.000702 AC: 99 AN: 140964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000490

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.000626

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00402

Gnomad SAS AF: 0.00489

Gnomad FIN AF: 0.00206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00668 AC: 449 AN: 67262 Hom.: 0 Cov.: 0 AF XY: 0.00644 AC XY: 218 AN XY: 33856

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00945 AC: 19 AN: 2010

American (AMR) AF: 0.00800 AC: 17 AN: 2124

Ashkenazi Jewish (ASJ) AF: 0.00818 AC: 22 AN: 2690

East Asian (EAS) AF: 0.00631 AC: 38 AN: 6026

South Asian (SAS) AF: 0.00313 AC: 3 AN: 960

European-Finnish (FIN) AF: 0.00503 AC: 27 AN: 5368

Middle Eastern (MID) AF: 0.000765 AC: 1 AN: 1308

European-Non Finnish (NFE) AF: 0.00681 AC: 287 AN: 42116

Other (OTH) AF: 0.00751 AC: 35 AN: 4660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000695 AC: 98 AN: 141066 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 46 AN XY: 68416

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000488 AC: 19 AN: 38896

American (AMR) AF: 0.000625 AC: 9 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00403 AC: 17 AN: 4216

South Asian (SAS) AF: 0.00464 AC: 19 AN: 4096

European-Finnish (FIN) AF: 0.00206 AC: 18 AN: 8728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000233 AC: 15 AN: 64270

Other (OTH) AF: 0.00 AC: 0 AN: 2008

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.49
PromoterAI		0.015	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: rs1662614831; hg19: chr2-16080813;