Genetic Variant MT2A:c.-77A>G (chr16-56608579-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005953.5(MT2A):c.-77A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,581,096 control chromosomes in the GnomAD database, including 3,249 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 0.047 ( 223 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3026 hom. )

Consequence

MT2A
NM_005953.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.997

Publications

67 publications found

Variant links:

Genes affected

MT2A (HGNC:7406): (metallothionein 2A) This gene is a member of the metallothionein family of genes. Proteins encoded by this gene family are low in molecular weight, are cysteine-rich, lack aromatic residues, and bind divalent heavy metal ions, altering the intracellular concentration of heavy metals in the cell. These proteins act as anti-oxidants, protect against hydroxyl free radicals, are important in homeostatic control of metal in the cell, and play a role in detoxification of heavy metals. The encoded protein interacts with the protein encoded by the homeobox containing 1 gene in some cell types, controlling intracellular zinc levels, affecting apoptotic and autophagy pathways. Some polymorphisms in this gene are associated with an increased risk of cancer. [provided by RefSeq, Sep 2017]

MT2A links:

LOC124903695 (HGNC:):

LOC124903695 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005953.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT2A	NM_005953.5	MANE Select	c.-77A>G		upstream_gene	N/A	NP_005944.1	P02795

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MT2A	ENST00000245185.6	TSL:1 MANE Select	c.-77A>G	upstream_gene	N/A	ENSP00000245185.5	P02795
MT2A	ENST00000561491.1	TSL:2	c.-77A>G	upstream_gene	N/A	ENSP00000456804.1	H3BSP9
MT2A	ENST00000931885.1		c.-77A>G	upstream_gene	N/A	ENSP00000601944.1

Frequencies

GnomAD3 genomes

AF:

0.0474

AC:

7193

AN:

151726

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0590

Gnomad ASJ

AF:

0.0522

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0554

Gnomad OTH

AF:

0.0411

GnomAD4 exome

AF:

0.0605

AC:

86459

AN:

1429256

Hom.:

3026

Cov.:

AF XY:

0.0619

AC XY:

44129

AN XY:

713278

show subpopulations

African (AFR)

AF:

0.0151

AC:

494

AN:

32746

American (AMR)

AF:

0.0910

AC:

4056

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.0514

AC:

1333

AN:

25916

East Asian (EAS)

AF:

0.0959

AC:

3791

AN:

39532

South Asian (SAS)

AF:

0.105

AC:

8951

AN:

85486

European-Finnish (FIN)

AF:

0.0535

AC:

2820

AN:

52710

Middle Eastern (MID)

AF:

0.0539

AC:

303

AN:

5618

European-Non Finnish (NFE)

AF:

0.0564

AC:

61116

AN:

1083328

Other (OTH)

AF:

0.0606

AC:

3595

AN:

59360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

4091

8182

12273

16364

20455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2332

4664

6996

9328

11660

<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:

0.0474

AC:

7191

AN:

151840

Hom.:

223

Cov.:

AF XY:

0.0487

AC XY:

3613

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.0164

AC:

678

AN:

41380

American (AMR)

AF:

0.0589

AC:

900

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0522

AC:

181

AN:

3470

East Asian (EAS)

AF:

0.103

AC:

528

AN:

5120

South Asian (SAS)

AF:

0.101

AC:

483

AN:

4802

European-Finnish (FIN)

AF:

0.0513

AC:

542

AN:

10566

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0554

AC:

3760

AN:

67914

Other (OTH)

AF:

0.0407

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

355

709

1064

1418

1773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0511

Hom.:

Bravo

AF:

0.0479

Asia WGS

AF:

0.0750

AC:

261

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.1

(source)

DANN

Benign

0.46

PhyloP100

-1.0

PromoterAI

0.014

Neutral

(source)

Mutation Taster

=300/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over