NM_002412.5:c.126-57395G>A

Variant names:

• chr10-129650500-G-A
• rs2008387
• NM_002412.5:c.126-57395G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002412.5(MGMT):​c.126-57395G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,988 control chromosomes in the GnomAD database, including 10,184 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 0.36 (10184 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.731
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002412.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	NM_002412.5	MANE Select	c.126-57395G>A		intron	N/A	NP_002403.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	ENST00000651593.1	MANE Select	c.126-57395G>A		intron	N/A	ENSP00000498729.1
	MGMT	ENST00000306010.8	TSL:1	c.219-57395G>A		intron	N/A	ENSP00000302111.7
	MGMT	ENST00000897068.1		c.126-57395G>A		intron	N/A	ENSP00000567127.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54267 AN: 151868 Hom.: 10170 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.357 AC: 54318 AN: 151988 Hom.: 10184 Cov.: 32 AF XY: 0.357 AC XY: 26553 AN XY: 74310

African (AFR) AF: 0.417 AC: 17264 AN: 41428

American (AMR) AF: 0.367 AC: 5610 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1281 AN: 3472

East Asian (EAS) AF: 0.0579 AC: 300 AN: 5178

South Asian (SAS) AF: 0.204 AC: 983 AN: 4812

European-Finnish (FIN) AF: 0.427 AC: 4507 AN: 10554

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23159 AN: 67954

Other (OTH) AF: 0.337 AC: 711 AN: 2108

Alfa AF: 0.366 Hom.: 1792

Bravo AF: 0.358

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.78
PhyloP100		0.73
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: rs2008387; hg19: chr10-131448764;