10-129536340-G-A

Variant names:

• chr10-129536340-G-A
• rs2020893
• NM_002412.5:c.88G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002412.5(MGMT):​c.88G>A​(p.Glu30Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,614,056 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: MGMT NM_002412.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.21
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006732762).
• BP6: Variant 10-129536340-G-A is Benign according to our data. Variant chr10-129536340-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 597465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.88G>A	p.Glu30Lys	missense_variant	Exon 2 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.88G>A	p.Glu30Lys	missense_variant	Exon 2 of 5		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.181G>A	p.Glu61Lys	missense_variant	Exon 2 of 5	1		ENSP00000302111.7
MGMT	ENST00000482547.1	n.135G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
MGMT	ENST00000482653.1	n.168G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000758 AC: 190 AN: 250558 AF XY: 0.000576

Gnomad AFR exome AF: 0.00974

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461748 Hom.: 2 Cov.: 30 AF XY: 0.000223 AC XY: 162 AN XY: 727176

African (AFR) AF: 0.0105 AC: 350 AN: 33466

American (AMR) AF: 0.000739 AC: 33 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111976

Other (OTH) AF: 0.000530 AC: 32 AN: 60388

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74474

African (AFR) AF: 0.0104 AC: 432 AN: 41558

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00136 Hom.: 3

Bravo AF: 0.00325

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000848 AC: 103

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jun 20, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.9
DANN	Benign	0.78
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.046
Sift	Benign	0.68	T
Sift4G	Benign	0.73	T
Vest4		0.11
MVP		0.20
MPC		0.065
ClinPred		0.00076	T
GERP RS		-0.056
gMVP		0.67
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2020893; hg19: chr10-131334604; COSMIC: COSV100022683;