dbSNP rs2308327: MGMT:p.Lys178Arg (chr10-129766906-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002412.5(MGMT):c.533A>G(p.Lys178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,358 control chromosomes in the GnomAD database, including 12,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 826 hom., cov: 34)

Exomes 𝑓: 0.12 ( 11511 hom. )

Consequence

MGMT
NM_002412.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.18

Publications

75 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015718937).

BP6

Variant 10-129766906-A-G is Benign according to our data. Variant chr10-129766906-A-G is described in ClinVar as Benign. ClinVar VariationId is 1230786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5 link	c.533A>G	p.Lys178Arg	missense_variant	Exon 5 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.533A>G	p.Lys178Arg	missense_variant	Exon 5 of 5		NM_002412.5	ENSP00000498729.1		P16455
MGMT	ENST00000306010.8 link	c.626A>G	p.Lys209Arg	missense_variant	Exon 5 of 5	1		ENSP00000302111.7		B4DEE8

Frequencies

GnomAD3 genomes

AF:

0.0872

AC:

13274

AN:

152220

Hom.:

827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.0719

Gnomad ASJ

AF:

0.0764

Gnomad EAS

AF:

0.0118

Gnomad SAS

AF:

0.0752

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.0865

GnomAD2 exomes

AF:

0.0937

AC:

23396

AN:

249700

AF XY:

0.0979

show subpopulations

Gnomad AFR exome

AF:

0.0190

Gnomad AMR exome

AF:

0.0474

Gnomad ASJ exome

AF:

0.0882

Gnomad EAS exome

AF:

0.00887

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.0984

GnomAD4 exome

AF:

0.120

AC:

174969

AN:

1461020

Hom.:

11511

Cov.:

AF XY:

0.119

AC XY:

86680

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.0180

AC:

604

AN:

33478

American (AMR)

AF:

0.0494

AC:

2211

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0884

AC:

2311

AN:

26136

East Asian (EAS)

AF:

0.00496

AC:

197

AN:

39698

South Asian (SAS)

AF:

0.0831

AC:

7163

AN:

86242

European-Finnish (FIN)

AF:

0.121

AC:

6364

AN:

52716

Middle Eastern (MID)

AF:

0.0889

AC:

512

AN:

5760

European-Non Finnish (NFE)

AF:

0.134

AC:

149211

AN:

1111898

Other (OTH)

AF:

0.106

AC:

6396

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

8109

16217

24326

32434

40543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5248

10496

15744

20992

26240

<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:

0.0871

AC:

13270

AN:

152338

Hom.:

826

Cov.:

AF XY:

0.0857

AC XY:

6387

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0224

AC:

932

AN:

41594

American (AMR)

AF:

0.0717

AC:

1098

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0764

AC:

265

AN:

3470

East Asian (EAS)

AF:

0.0116

AC:

AN:

5168

South Asian (SAS)

AF:

0.0758

AC:

366

AN:

4826

European-Finnish (FIN)

AF:

0.130

AC:

1380

AN:

10628

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8771

AN:

68024

Other (OTH)

AF:

0.0866

AC:

183

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

631

1262

1894

2525

3156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.114

Hom.:

4795

Bravo

AF:

0.0799

TwinsUK

AF:

0.143

AC:

532

ALSPAC

AF:

0.129

AC:

498

ESP6500AA

AF:

0.0222

AC:

ESP6500EA

AF:

0.128

AC:

1105

ExAC

AF:

0.0932

AC:

11306

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.128

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17234722, 18812520) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.9

(source)

DANN

Benign

0.95

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.95

PhyloP100

2.2

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.92

REVEL

Benign

0.073

Sift

Benign

0.046

Sift4G

Benign

0.12

Vest4

0.057

MPC

0.043

ClinPred

0.0094

GERP RS

-3.6

gMVP

0.31

Mutation Taster

=98/2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over