Genetic Variant NM_002467.6:c.302A>G (chr8-127738519-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2PM5PP2BP4_Moderate

The NM_002467.6(MYC):c.302A>G(p.Asn101Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. N101T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MYC
NM_002467.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.884

Publications

0 publications found

Variant links:

COSMIC-nc: COSV52369089

Genes affected

MYC (HGNC:7553): (MYC proto-oncogene, bHLH transcription factor) This gene is a proto-oncogene and encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation. The encoded protein forms a heterodimer with the related transcription factor MAX. This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes. Amplification of this gene is frequently observed in numerous human cancers. Translocations involving this gene are associated with Burkitt lymphoma and multiple myeloma in human patients. There is evidence to show that translation initiates both from an upstream, in-frame non-AUG (CUG) and a downstream AUG start site, resulting in the production of two isoforms with distinct N-termini. [provided by RefSeq, Aug 2017]

MYC links:

CASC11 (HGNC:48939): (cancer susceptibility 11)

CASC11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-127738519-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12575.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2227 (below the threshold of 3.09). Trascript score misZ: 1.518 (below the threshold of 3.09). GenCC associations: The gene is linked to Burkitt lymphoma.

BP4

Computational evidence support a benign effect (MetaRNN=0.15065399).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002467.6. 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
	MYC	NM_002467.6	MANE Select	c.302A>G	p.Asn101Ser	missense	Exon 2 of 3	NP_002458.2	P01106-2
	MYC	NM_001354870.1		c.299A>G	p.Asn100Ser	missense	Exon 2 of 3	NP_001341799.1	P01106-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYC	ENST00000621592.8	TSL:1 MANE Select	c.302A>G	p.Asn101Ser	missense	Exon 2 of 3	ENSP00000478887.2	P01106-2
MYC	ENST00000524013.2	TSL:1	c.299A>G	p.Asn100Ser	missense	Exon 2 of 3	ENSP00000430235.2	P01106-3
MYC	ENST00000377970.6	TSL:1	c.257A>G	p.Asn86Ser	missense	Exon 2 of 3	ENSP00000367207.3	P01106-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.037

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

PhyloP100

0.88

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.040

REVEL

Benign

0.036

Sift

Uncertain

0.012

Sift4G

Benign

0.41

Polyphen

0.0070

Vest4

0.11

MutPred

0.33

Gain of phosphorylation at N86 (P = 0.0123)

MVP

0.87

ClinPred

0.053

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.099

gMVP

0.17

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over