rs2296675

Variant names:

• chr10-129766734-A-G
• rs2296675
• NM_002412.5:c.415-54A>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.415-54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,523,598 control chromosomes in the GnomAD database, including 14,842 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 0.13 (1272 hom., cov: 34)
  • Exomes 𝑓: 0.14 (13570 hom.)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53
• Publications: 8 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 (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.415-54A>G		intron_variant	Intron 4 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.415-54A>G		intron_variant	Intron 4 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.508-54A>G		intron_variant	Intron 4 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19388 AN: 152134 Hom.: 1271 Cov.: 34

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.138 AC: 188660 AN: 1371346 Hom.: 13570 AF XY: 0.139 AC XY: 94339 AN XY: 678666

African (AFR) AF: 0.102 AC: 3223 AN: 31604

American (AMR) AF: 0.115 AC: 4449 AN: 38560

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3674 AN: 23540

East Asian (EAS) AF: 0.120 AC: 4501 AN: 37356

South Asian (SAS) AF: 0.164 AC: 12586 AN: 76760

European-Finnish (FIN) AF: 0.0804 AC: 3985 AN: 49562

Middle Eastern (MID) AF: 0.226 AC: 930 AN: 4112

European-Non Finnish (NFE) AF: 0.140 AC: 147179 AN: 1052930

Other (OTH) AF: 0.143 AC: 8133 AN: 56922

GnomAD4 genome AF: 0.127 AC: 19409 AN: 152252 Hom.: 1272 Cov.: 34 AF XY: 0.126 AC XY: 9375 AN XY: 74444

African (AFR) AF: 0.106 AC: 4390 AN: 41578

American (AMR) AF: 0.140 AC: 2150 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 526 AN: 3468

East Asian (EAS) AF: 0.123 AC: 634 AN: 5162

South Asian (SAS) AF: 0.155 AC: 745 AN: 4818

European-Finnish (FIN) AF: 0.0817 AC: 867 AN: 10612

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9643 AN: 67988

Other (OTH) AF: 0.145 AC: 306 AN: 2116

Alfa AF: 0.136 Hom.: 490

Bravo AF: 0.130

Asia WGS AF: 0.127 AC: 443 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	0.037
DANN	Benign	0.55
PhyloP100		-2.5
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: rs2296675; hg19: chr10-131564998; COSMIC: COSV60027861; COSMIC: COSV60027861;