dbSNP rs12356501: MGMT:c.-13+292C>T (chr10-129467588-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002412.5(MGMT):c.-13+292C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 259,636 control chromosomes in the GnomAD database, including 40,117 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 0.50 ( 21488 hom., cov: 33)

Exomes 𝑓: 0.58 ( 18629 hom. )

Consequence

MGMT
NM_002412.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.108

Publications

13 publications found

Variant links:

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]

MGMT links:

ENSG00000296036 (HGNC:):

ENSG00000296036 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5 link	c.-13+292C>T		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 link	c.-13+292C>T		intron_variant	Intron 1 of 4		NM_002412.5	ENSP00000498729.1

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

76040

AN:

151938

Hom.:

21488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.555

Gnomad AMR

AF:

0.563

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.658

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.609

Gnomad OTH

AF:

0.548

GnomAD4 exome

AF:

0.576

AC:

62004

AN:

107580

Hom.:

18629

AF XY:

0.574

AC XY:

29469

AN XY:

51310

show subpopulations

African (AFR)

AF:

0.173

AC:

383

AN:

2212

American (AMR)

AF:

0.516

AC:

AN:

128

Ashkenazi Jewish (ASJ)

AF:

0.577

AC:

374

AN:

648

East Asian (EAS)

AF:

0.644

AC:

278

AN:

432

South Asian (SAS)

AF:

0.560

AC:

1174

AN:

2098

European-Finnish (FIN)

AF:

0.656

AC:

AN:

Middle Eastern (MID)

AF:

0.539

AC:

124

AN:

230

European-Non Finnish (NFE)

AF:

0.586

AC:

57495

AN:

98184

Other (OTH)

AF:

0.578

AC:

2089

AN:

3616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1286

2571

3857

5142

6428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2124

4248

6372

8496

10620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.500

AC:

76050

AN:

152056

Hom.:

21488

Cov.:

AF XY:

0.505

AC XY:

37560

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.218

AC:

9067

AN:

41502

American (AMR)

AF:

0.562

AC:

8594

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

2191

AN:

3472

East Asian (EAS)

AF:

0.632

AC:

3240

AN:

5124

South Asian (SAS)

AF:

0.568

AC:

2736

AN:

4816

European-Finnish (FIN)

AF:

0.658

AC:

6974

AN:

10592

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.609

AC:

41397

AN:

67946

Other (OTH)

AF:

0.549

AC:

1160

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1725

3450

5176

6901

8626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.569

Hom.:

27733

Bravo

AF:

0.483

Asia WGS

AF:

0.582

AC:

2025

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.2

(source)

DANN

Benign

0.64

PhyloP100

-0.11

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over