10-129521544-C-G

Variant names:

• chr10-129521544-C-G
• rs12256667
• NM_002412.5:c.-12-14697C>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.-12-14697C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,024 control chromosomes in the GnomAD database, including 5,608 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 0.25 (5608 hom., cov: 34)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-12-14697C>G		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.-12-14697C>G		intron_variant	Intron 1 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.82-14697C>G		intron_variant	Intron 1 of 4	1		ENSP00000302111.7
MGMT	ENST00000482547.1	n.36-14697C>G		intron_variant	Intron 1 of 1	2
MGMT	ENST00000482653.1	n.69-14697C>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37682 AN: 151906 Hom.: 5599 Cov.: 34

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.0839

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.248 AC: 37738 AN: 152024 Hom.: 5608 Cov.: 34 AF XY: 0.249 AC XY: 18483 AN XY: 74320

African (AFR) AF: 0.423 AC: 17536 AN: 41420

American (AMR) AF: 0.240 AC: 3665 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3470

East Asian (EAS) AF: 0.323 AC: 1664 AN: 5148

South Asian (SAS) AF: 0.203 AC: 977 AN: 4818

European-Finnish (FIN) AF: 0.177 AC: 1877 AN: 10610

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10778 AN: 67962

Other (OTH) AF: 0.226 AC: 476 AN: 2108

Alfa AF: 0.219 Hom.: 548

Bravo AF: 0.262

Asia WGS AF: 0.273 AC: 950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.36
PhyloP100		0.45
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: rs12256667; hg19: chr10-131319808;