rs2296675

Positions:

• chr10-129766734-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002412.5(MGMT):​c.415-54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,523,598 control chromosomes in the GnomAD database, including 14,842 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1272 hom., cov: 34)
  • Exomes 𝑓: 0.14 (13570 hom.)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53

Genes affected

MGMT (HGNC:7059): (O-6-methylguanine-DNA methyltransferase) Alkylating agents are potent carcinogens that can result in cell death, mutation and cancer. The protein encoded by this gene is a DNA repair protein that is involved in cellular defense against mutagenesis and toxicity from alkylating agents. The protein catalyzes transfer of methyl groups from O(6)-alkylguanine and other methylated moieties of the DNA to its own molecule, which repairs the toxic lesions. Methylation of the genes promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.415-54A>G		intron_variant		ENST00000651593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.415-54A>G		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.508-54A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19388 AN: 152134 Hom.: 1271 Cov.: 34

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.138 AC: 188660 AN: 1371346 Hom.: 13570 AF XY: 0.139 AC XY: 94339 AN XY: 678666

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.127 AC: 19409 AN: 152252 Hom.: 1272 Cov.: 34 AF XY: 0.126 AC XY: 9375 AN XY: 74444

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.0817

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.145

Alfa AF: 0.138 Hom.: 264

Bravo AF: 0.130

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.037
DANN	Benign	0.55

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: rs2296675; hg19: chr10-131564998; COSMIC: COSV60027861; COSMIC: COSV60027861;