10-129477956-T-C

Variant names:

• chr10-129477956-T-C
• rs1711662
• NM_002412.5:c.-13+10660T>C

Variant summary

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

The NM_002412.5(MGMT):​c.-13+10660T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 152,132 control chromosomes in the GnomAD database, including 43,662 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 0.76 (43662 hom., cov: 31)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.941 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.-13+10660T>C		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.-13+10660T>C		intron	N/A	ENSP00000498729.1
	MGMT	ENST00000306010.8	TSL:1	c.81+10660T>C		intron	N/A	ENSP00000302111.7
	MGMT	ENST00000482547.1	TSL:2	n.35+10660T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114825 AN: 152014 Hom.: 43636 Cov.: 31

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.783

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.769

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

GnomAD4 genome AF: 0.755 AC: 114898 AN: 152132 Hom.: 43662 Cov.: 31 AF XY: 0.759 AC XY: 56412 AN XY: 74356

African (AFR) AF: 0.773 AC: 32073 AN: 41516

American (AMR) AF: 0.757 AC: 11580 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2576 AN: 3468

East Asian (EAS) AF: 0.963 AC: 4970 AN: 5160

South Asian (SAS) AF: 0.834 AC: 4026 AN: 4830

European-Finnish (FIN) AF: 0.741 AC: 7828 AN: 10568

Middle Eastern (MID) AF: 0.784 AC: 229 AN: 292

European-Non Finnish (NFE) AF: 0.727 AC: 49431 AN: 67976

Other (OTH) AF: 0.770 AC: 1628 AN: 2114

Alfa AF: 0.743 Hom.: 7136

Bravo AF: 0.757

Asia WGS AF: 0.889 AC: 3091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.012
DANN	Benign	0.47
PhyloP100		-1.9
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: rs1711662; hg19: chr10-131276220;