8-127738294-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (72 hom., cov: 33)
  • Exomes 𝑓: 0.033 (940 hom.)
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.19

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082629025).
• BP6: Variant 8-127738294-A-G is Benign according to our data. Variant chr8-127738294-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1679939.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3651 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6	c.77A>G	p.Asn26Ser	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1	c.74A>G	p.Asn25Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8	c.77A>G	p.Asn26Ser	missense_variant	2/3	1	NM_002467.6	A2

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

GnomAD3 exomes AF: 0.0230 AC: 5750 AN: 249536 Hom.: 91 AF XY: 0.0231 AC XY: 3117 AN XY: 134904

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 SAS exome AF: 0.00379

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

Gnomad4 AFR exome AF: 0.00683

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.0160

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0278

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

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0363

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0336 Hom.: 259

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic Hodgkin lymphoma Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pathology Department, Puerta del Mar University Hospital

Oct 01, 2021

- -

MYC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

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	T
BayesDel_noAF	Benign	-0.60
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
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	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
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
Polyphen		0.98	.;.;.;D;.;.
Vest4		0.14
ClinPred		0.035	T
GERP RS		3.9
Varity_R		0.42
gMVP		0.50

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

LitVar

Other links and lift over

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