rs12268840

Positions:

• chr10-129527035-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.-12-9206C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,230 control chromosomes in the GnomAD database, including 4,284 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 0.22 (4284 hom., cov: 34)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338

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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-12-9206C>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.-12-9206C>T		intron_variant			NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.82-9206C>T		intron_variant		1		ENSP00000302111
MGMT	ENST00000482547.1	n.36-9206C>T		intron_variant, non_coding_transcript_variant		2
MGMT	ENST00000482653.1	n.69-9206C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33512 AN: 152112 Hom.: 4280 Cov.: 34

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.214

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33533 AN: 152230 Hom.: 4284 Cov.: 34 AF XY: 0.219 AC XY: 16279 AN XY: 74432

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.213

Alfa AF: 0.276 Hom.: 5412

Bravo AF: 0.213

Asia WGS AF: 0.0970 AC: 336 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	4.5
DANN	Benign	0.81

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: rs12268840; hg19: chr10-131325299;