12-53482836-C-G

Variant names:

• chr12-53482836-C-G
• NM_001193511.2:c.1967G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001193511.2(MAP3K12):​c.1967G>C​(p.Arg656Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,538 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAP3K12 NM_001193511.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K12	NM_001193511.2	c.1967G>C	p.Arg656Pro	missense_variant	Exon 11 of 14	ENST00000547488.6	NP_001180440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K12	ENST00000547488.6	c.1967G>C	p.Arg656Pro	missense_variant	Exon 11 of 14	2	NM_001193511.2	ENSP00000449038.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458538 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.54
MutPred		0.39		Gain of catalytic residue at T626 (P = 0.0014);.;.;
MVP		0.66
MPC		0.30
ClinPred		0.82	D
GERP RS		4.1
Varity_R		0.33
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53876620;