Genetic Variant MAP3K12:p.Leu781Arg (chr12-53482179-A-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001193511.2(MAP3K12):c.2342T>G(p.Leu781Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MAP3K12
NM_001193511.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Publications

0 publications found

Variant links:

Genes affected

MAP3K12 (HGNC:6851): (mitogen-activated protein kinase kinase kinase 12) This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.[provided by RefSeq, Jul 2010]

MAP3K12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06884602).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193511.2. 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
	MAP3K12	NM_001193511.2	MANE Select	c.2342T>G	p.Leu781Arg	missense	Exon 13 of 14	NP_001180440.1	Q12852-2
	MAP3K12	NM_006301.4		c.2243T>G	p.Leu748Arg	missense	Exon 14 of 15	NP_006292.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K12	ENST00000547488.6	TSL:2 MANE Select	c.2342T>G	p.Leu781Arg	missense	Exon 13 of 14	ENSP00000449038.1	Q12852-2
MAP3K12	ENST00000267079.6	TSL:1	c.2243T>G	p.Leu748Arg	missense	Exon 14 of 15	ENSP00000267079.2	Q12852-1
MAP3K12	ENST00000552365.1	TSL:1	n.*1072T>G		non_coding_transcript_exon	Exon 13 of 14	ENSP00000447889.1	F8VUG4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251484

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000579

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.051

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.81

M_CAP

Benign

0.012

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.080

REVEL

Benign

0.036

Sift

Benign

0.057

Sift4G

Benign

0.23

Polyphen

0.41

Vest4

0.24

MutPred

0.30

Gain of MoRF binding (P = 0.0249)

MVP

0.19

MPC

0.81

ClinPred

0.32

GERP RS

1.9

Varity_R

0.045

gMVP

0.43

Mutation Taster

=74/26

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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