8-127738294-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_002467.6(MYC):c.77A>G(p.Asn26Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0319 in 1,610,196 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.024 ( 72 hom., cov: 33)

Exomes 𝑓: 0.033 ( 940 hom. )

Consequence

MYC
NM_002467.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 5.19

Publications

99 publications found

Variant links:

COSMIC-nc: COSV52371145

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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=0.0082629025).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3648/152296) while in subpopulation NFE AF = 0.0363 (2466/68022). AF 95% confidence interval is 0.0351. There are 72 homozygotes in GnomAd4. There are 1653 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 72 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYC	NM_002467.6 link	c.77A>G	p.Asn26Ser	missense_variant	Exon 2 of 3	ENST00000621592.8	NP_002458.2
MYC	NM_001354870.1 link	c.74A>G	p.Asn25Ser	missense_variant	Exon 2 of 3		NP_001341799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYC	ENST00000621592.8 link	c.77A>G	p.Asn26Ser	missense_variant	Exon 2 of 3	1	NM_002467.6	ENSP00000478887.2

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3651

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0230

AC:

5750

AN:

249536

AF XY:

0.0231

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0427

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0289

GnomAD4 exome

AF:

0.0327

AC:

47736

AN:

1457900

Hom.:

940

Cov.:

AF XY:

0.0318

AC XY:

23053

AN XY:

724576

show subpopulations

African (AFR)

AF:

0.00683

AC:

228

AN:

33404

American (AMR)

AF:

0.0207

AC:

918

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.0425

AC:

1104

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00392

AC:

337

AN:

85990

European-Finnish (FIN)

AF:

0.0160

AC:

855

AN:

53336

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0383

AC:

42527

AN:

1109196

Other (OTH)

AF:

0.0278

AC:

1672

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

2761

5522

8282

11043

13804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1616

3232

4848

6464

8080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0240

AC:

3648

AN:

152296

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1653

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41568

American (AMR)

AF:

0.0282

AC:

431

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00270

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0363

AC:

2466

AN:

68022

Other (OTH)

AF:

0.0298

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

196

392

588

784

980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0319

Hom.:

433

Bravo

AF:

0.0251

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0397

AC:

341

ExAC

AF:

0.0221

AC:

2686

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0380

EpiControl

AF:

0.0401

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic Hodgkin lymphoma

Uncertain:1

Oct 01, 2021

Pathology Department, Puerta del Mar University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

MYC-related disorder

Benign:1

Nov 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T;T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

T;T;T;T;T;T

MetaRNN

Benign

0.0083

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;.;M;.;.

PhyloP100

5.2

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;.;.;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.018

D;D;.;.;D;.

Sift4G

Benign

0.081

T;D;D;T;D;D

Vest4

0.14

ClinPred

0.035

GERP RS

3.9

Varity_R

0.42

gMVP

0.50

Mutation Taster

=81/19

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over