8-127738281-T-C

Position:

• chr8-127738281-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002467.6(MYC):​c.64T>C​(p.Phe22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,604,432 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (23 hom.)
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.635

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024340153).
• BP6: Variant 8-127738281-T-C is Benign according to our data. Variant chr8-127738281-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 722844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6	c.64T>C	p.Phe22Leu	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1	c.61T>C	p.Phe21Leu	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8	c.64T>C	p.Phe22Leu	missense_variant	2/3	1	NM_002467.6	A2

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00278 AC: 689 AN: 247448 Hom.: 6 AF XY: 0.00268 AC XY: 358 AN XY: 133742

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00631

GnomAD4 exome AF: 0.00193 AC: 2797 AN: 1452110 Hom.: 23 Cov.: 32 AF XY: 0.00193 AC XY: 1393 AN XY: 720620

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00198

Gnomad4 ASJ exome AF: 0.0391

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00464

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74492

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00302 Hom.: 5

Bravo AF: 0.00205

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MYC: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.21	.;T;T;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	.;.;.;N;.;.
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.1	N;N;.;.;N;.
REVEL	Benign	0.061
Sift	Benign	0.76	T;T;.;.;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0010	.;.;.;B;.;.
Vest4		0.11
MutPred		0.47		Gain of glycosylation at S6 (P = 0.091);.;.;Gain of glycosylation at S6 (P = 0.091);.;.;
MVP		0.22
ClinPred		0.00043	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.15

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: rs146505192; hg19: chr8-128750527; COSMIC: COSV52370221; COSMIC: COSV52370221;