rs12268840

Variant names:

• chr10-129527035-C-T
• rs12268840
• NM_002412.5:c.-12-9206C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-12-9206C>T		intron_variant	Intron 1 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.-12-9206C>T		intron_variant	Intron 1 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.82-9206C>T		intron_variant	Intron 1 of 4	1		ENSP00000302111.7
MGMT	ENST00000482547.1	n.36-9206C>T		intron_variant	Intron 1 of 1	2
MGMT	ENST00000482653.1	n.69-9206C>T		intron_variant	Intron 1 of 2	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

African (AFR) AF: 0.113 AC: 4684 AN: 41548

American (AMR) AF: 0.234 AC: 3574 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3468

East Asian (EAS) AF: 0.0375 AC: 194 AN: 5178

South Asian (SAS) AF: 0.170 AC: 821 AN: 4828

European-Finnish (FIN) AF: 0.300 AC: 3176 AN: 10596

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19353 AN: 68006

Other (OTH) AF: 0.213 AC: 450 AN: 2114

Alfa AF: 0.268 Hom.: 6887

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
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12268840; hg19: chr10-131325299;