10-129651223-C-G

Variant names:

• chr10-129651223-C-G
• rs2026976
• NM_002412.5:c.126-56672C>G

Variant summary

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

The NM_002412.5(MGMT):​c.126-56672C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,038 control chromosomes in the GnomAD database, including 6,741 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 0.29 (6741 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.430
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-56672C>G		intron_variant	Intron 2 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.126-56672C>G		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-56672C>G		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43859 AN: 151920 Hom.: 6734 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.289 AC: 43883 AN: 152038 Hom.: 6741 Cov.: 32 AF XY: 0.290 AC XY: 21549 AN XY: 74308

African (AFR) AF: 0.228 AC: 9453 AN: 41504

American (AMR) AF: 0.298 AC: 4550 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1136 AN: 3470

East Asian (EAS) AF: 0.0451 AC: 233 AN: 5162

South Asian (SAS) AF: 0.193 AC: 929 AN: 4814

European-Finnish (FIN) AF: 0.407 AC: 4301 AN: 10560

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22257 AN: 67940

Other (OTH) AF: 0.277 AC: 584 AN: 2110

Alfa AF: 0.190 Hom.: 427

Bravo AF: 0.280

Asia WGS AF: 0.118 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.81
DANN	Benign	0.67
PhyloP100		-0.43
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: rs2026976; hg19: chr10-131449487;