chr8-127738294-A-G

Variant names:

• chr8-127738294-A-G
• rs4645959
• NM_002467.6:c.77A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 5.19
• Publications: 99 publications found

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]

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

ACMG classification

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYC	NM_002467.6	MANE Select	c.77A>G	p.Asn26Ser	missense	Exon 2 of 3	NP_002458.2
	MYC	NM_001354870.1		c.74A>G	p.Asn25Ser	missense	Exon 2 of 3	NP_001341799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYC	ENST00000621592.8	TSL:1 MANE Select	c.77A>G	p.Asn26Ser	missense	Exon 2 of 3	ENSP00000478887.2
	MYC	ENST00000524013.2	TSL:1	c.74A>G	p.Asn25Ser	missense	Exon 2 of 3	ENSP00000430235.2
	MYC	ENST00000377970.6	TSL:1	c.32A>G	p.Asn11Ser	missense	Exon 2 of 3	ENSP00000367207.3

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3651 AN: 152178 Hom.: 72 Cov.: 33

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

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.: 32 AF XY: 0.0318 AC XY: 23053 AN XY: 724576

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: 0 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: 95 AN: 5748

European-Non Finnish (NFE) AF: 0.0383 AC: 42527 AN: 1109196

Other (OTH) AF: 0.0278 AC: 1672 AN: 60194

GnomAD4 genome AF: 0.0240 AC: 3648 AN: 152296 Hom.: 72 Cov.: 33 AF XY: 0.0222 AC XY: 1653 AN XY: 74458

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: 1 AN: 5172

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4818

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0363 AC: 2466 AN: 68022

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

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: 35

ESP6500EA AF: 0.0397 AC: 341

ExAC AF: 0.0221 AC: 2686

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.0380

EpiControl AF: 0.0401

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.23
Sift	Uncertain	0.018	D
Sift4G	Benign	0.081	T
Polyphen		0.98	D
Vest4		0.14
ClinPred		0.035	T
GERP RS		3.9
Varity_R		0.42
gMVP		0.50
Mutation Taster		=81/19	polymorphism (auto)

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: rs4645959; hg19: chr8-128750540; COSMIC: COSV52371145;