rs12356501

Positions:

• chr10-129467588-C-T

Variant summary

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

The NM_002412.5(MGMT):​c.-13+292C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 259,636 control chromosomes in the GnomAD database, including 40,117 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 0.50 (21488 hom., cov: 33)
  • Exomes 𝑓: 0.58 (18629 hom.)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108

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]

MGMT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-13+292C>T		intron_variant		ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.-13+292C>T		intron_variant			NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.81+292C>T		intron_variant		1		ENSP00000302111.7
MGMT	ENST00000482547.1	n.35+292C>T		intron_variant		2
MGMT	ENST00000482653.1	n.68+292C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 76040 AN: 151938 Hom.: 21488 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.576 AC: 62004 AN: 107580 Hom.: 18629 AF XY: 0.574 AC XY: 29469 AN XY: 51310

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.577

Gnomad4 EAS exome AF: 0.644

Gnomad4 SAS exome AF: 0.560

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.500 AC: 76050 AN: 152056 Hom.: 21488 Cov.: 33 AF XY: 0.505 AC XY: 37560 AN XY: 74306

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.631

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.549

Alfa AF: 0.585 Hom.: 22049

Bravo AF: 0.483

Asia WGS AF: 0.582 AC: 2025 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Benign	0.64

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: rs12356501; hg19: chr10-131265852;