chr10-129708014-C-G

Variant names:

• chr10-129708014-C-G
• rs761952141
• NM_002412.5:c.245C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002412.5(MGMT):​c.245C>G​(p.Pro82Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P82L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MGMT NM_002412.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55
• Publications: 1 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]

LOC105378560 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.245C>G	p.Pro82Arg	missense_variant	Exon 3 of 5	ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3	n.-36C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.245C>G	p.Pro82Arg	missense_variant	Exon 3 of 5		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.338C>G	p.Pro113Arg	missense_variant	Exon 3 of 5	1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.406C>G		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.80	T
PhyloP100		6.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Vest4		0.69
MutPred		0.51		Gain of solvent accessibility (P = 0.0411);
MVP		0.47
MPC		0.34
ClinPred		0.99	D
GERP RS		4.8
gMVP		0.77
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs761952141; hg19: chr10-131506278; COSMIC: COSV100024283;