8-127738361-G-A

Position:

• chr8-127738361-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002467.6(MYC):​c.144G>A​(p.Gln48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,602,308 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: MYC NM_002467.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0210

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063643754).
• BP6: Variant 8-127738361-G-A is Benign according to our data. Variant chr8-127738361-G-A is described in ClinVar as [Benign]. Clinvar id is 791168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.021 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1661/152254) while in subpopulation AFR AF= 0.038 (1579/41566). AF 95% confidence interval is 0.0364. There are 28 homozygotes in gnomad4. There are 736 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYC	NM_002467.6	c.144G>A	p.Gln48=	synonymous_variant	2/3	ENST00000621592.8	NP_002458.2
MYC	NM_001354870.1	c.141G>A	p.Gln47=	synonymous_variant	2/3		NP_001341799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYC	ENST00000621592.8	c.144G>A	p.Gln48=	synonymous_variant	2/3	1	NM_002467.6	ENSP00000478887	A2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1658 AN: 152136 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00285 AC: 702 AN: 246430 Hom.: 12 AF XY: 0.00203 AC XY: 271 AN XY: 133366

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000429

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00131 AC: 1899 AN: 1450054 Hom.: 37 Cov.: 32 AF XY: 0.00121 AC XY: 876 AN XY: 721070

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.0000775

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.0109 AC: 1661 AN: 152254 Hom.: 28 Cov.: 33 AF XY: 0.00989 AC XY: 736 AN XY: 74436

Gnomad4 AFR AF: 0.0380

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00535 Hom.: 7

Bravo AF: 0.0122

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00336 AC: 407

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000879

EpiControl AF: 0.000536

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.0
DANN	Benign	0.95
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.23
MVP		0.58
ClinPred		0.036	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

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: rs61752959; hg19: chr8-128750607; COSMIC: COSV52374751; COSMIC: COSV52374751;