Genetic Variant ENST00000306010.8:c.66C>T (chr10-129467281-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

The ENST00000306010.8(MGMT):c.66C>T(p.Arg22Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,543,640 control chromosomes in the GnomAD database, including 3,472 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 0.050 ( 298 hom., cov: 33)

Exomes 𝑓: 0.065 ( 3174 hom. )

Consequence

MGMT
ENST00000306010.8 synonymous

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.412

Publications

78 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 -7 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5 link	c.-28C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1 link	c.-28C>T		5_prime_UTR_variant	Exon 1 of 5		NM_002412.5	ENSP00000498729.1		P16455

Frequencies

GnomAD3 genomes

AF:

0.0503

AC:

7658

AN:

152154

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0703

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0366

Gnomad FIN

AF:

0.0870

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0746

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0555

AC:

8097

AN:

145974

AF XY:

0.0564

show subpopulations

Gnomad AFR exome

AF:

0.00904

Gnomad AMR exome

AF:

0.0320

Gnomad ASJ exome

AF:

0.0714

Gnomad EAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.0851

Gnomad NFE exome

AF:

0.0740

Gnomad OTH exome

AF:

0.0643

GnomAD4 exome

AF:

0.0650

AC:

90419

AN:

1391368

Hom.:

3174

Cov.:

AF XY:

0.0649

AC XY:

44581

AN XY:

686666

show subpopulations

African (AFR)

AF:

0.00972

AC:

299

AN:

30772

American (AMR)

AF:

0.0340

AC:

1184

AN:

34820

Ashkenazi Jewish (ASJ)

AF:

0.0733

AC:

1828

AN:

24938

East Asian (EAS)

AF:

0.000145

AC:

AN:

34538

South Asian (SAS)

AF:

0.0419

AC:

3289

AN:

78554

European-Finnish (FIN)

AF:

0.0895

AC:

4227

AN:

47230

Middle Eastern (MID)

AF:

0.0537

AC:

304

AN:

5666

European-Non Finnish (NFE)

AF:

0.0706

AC:

76042

AN:

1077118

Other (OTH)

AF:

0.0561

AC:

3241

AN:

57732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

4320

8639

12959

17278

21598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0503

AC:

7660

AN:

152272

Hom.:

298

Cov.:

AF XY:

0.0509

AC XY:

3790

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0108

AC:

450

AN:

41576

American (AMR)

AF:

0.0370

AC:

566

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0703

AC:

244

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0370

AC:

179

AN:

4832

European-Finnish (FIN)

AF:

0.0870

AC:

922

AN:

10596

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0746

AC:

5070

AN:

67984

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

379

758

1136

1515

1894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0634

Hom.:

154

Bravo

AF:

0.0444

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Glioblastoma

Other:1

Mar 10, 2016

Database of Curated Mutations (DoCM)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.41

PromoterAI

0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.79

Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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ENST00000306010.8:c.66C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over