chr12-53483181-A-G

Variant names:

• chr12-53483181-A-G
• NM_001193511.2:c.1622T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193511.2(MAP3K12):​c.1622T>C​(p.Ile541Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K12 NM_001193511.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25432926).

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.1622T>C	p.Ile541Thr	missense	Exon 11 of 14	NP_001180440.1	Q12852-2
	MAP3K12	NM_006301.4		c.1523T>C	p.Ile508Thr	missense	Exon 12 of 15	NP_006292.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K12	ENST00000547488.6	TSL:2 MANE Select	c.1622T>C	p.Ile541Thr	missense	Exon 11 of 14	ENSP00000449038.1	Q12852-2
	MAP3K12	ENST00000267079.6	TSL:1	c.1523T>C	p.Ile508Thr	missense	Exon 12 of 15	ENSP00000267079.2	Q12852-1
	MAP3K12	ENST00000552365.1	TSL:1	n.*352T>C		non_coding_transcript_exon	Exon 11 of 14	ENSP00000447889.1	F8VUG4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1372438 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 673590

African (AFR) AF: 0.00 AC: 0 AN: 30370

American (AMR) AF: 0.00 AC: 0 AN: 29832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20056

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.00 AC: 0 AN: 70680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070830

Other (OTH) AF: 0.00 AC: 0 AN: 56434

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.052
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.76	T
Polyphen		0.88	P
Vest4		0.42
MutPred		0.27		Loss of stability (P = 0.0134)
MVP		0.23
MPC		0.45
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.46
Mutation Taster		=56/44	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

hg19: chr12-53876965;