rs2308327

Positions:

• chr10-129766906-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.087 (826 hom., cov: 34)
  • Exomes 𝑓: 0.12 (11511 hom.)
• Consequence: MGMT NM_002412.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.533A>G	p.Lys178Arg	missense_variant	5/5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.533A>G	p.Lys178Arg	missense_variant	5/5		NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.626A>G	p.Lys209Arg	missense_variant	5/5	1		ENSP00000302111

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13274 AN: 152220 Hom.: 827 Cov.: 34

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

GnomAD3 exomes AF: 0.0937 AC: 23396 AN: 249700 Hom.: 1374 AF XY: 0.0979 AC XY: 13258 AN XY: 135388

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 SAS exome AF: 0.0810

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.: 32 AF XY: 0.119 AC XY: 86680 AN XY: 726818

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.0494

Gnomad4 ASJ exome AF: 0.0884

Gnomad4 EAS exome AF: 0.00496

Gnomad4 SAS exome AF: 0.0831

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0871 AC: 13270 AN: 152338 Hom.: 826 Cov.: 34 AF XY: 0.0857 AC XY: 6387 AN XY: 74494

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0717

Gnomad4 ASJ AF: 0.0764

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0758

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.0866

Alfa AF: 0.117 Hom.: 2412

Bravo AF: 0.0799

TwinsUK AF: 0.143 AC: 532

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.0222 AC: 98

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2019	This variant is associated with the following publications: (PMID: 17234722, 18812520) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.9
DANN	Benign	0.95
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.073
Sift	Benign	0.046	D
Sift4G	Benign	0.12	T
Vest4		0.057
MPC		0.043
ClinPred		0.0094	T
GERP RS		-3.6
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs2308327; hg19: chr10-131565170; COSMIC: COSV60035775; COSMIC: COSV60035775;