12-53481229-A-G

Variant names:

• chr12-53481229-A-G
• NM_001193511.2:c.2632T>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.2632T>C​(p.Ser878Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K12 NM_001193511.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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]

PCBP2 (HGNC:8648): (poly(rC) binding protein 2) The protein encoded by this gene appears to be multifunctional. Along with PCBP-1 and hnRNPK, it is one of the major cellular poly(rC)-binding proteins. The encoded protein contains three K-homologous (KH) domains which may be involved in RNA binding. Together with PCBP-1, this protein also functions as a translational coactivator of poliovirus RNA via a sequence-specific interaction with stem-loop IV of the IRES, promoting poliovirus RNA replication by binding to its 5'-terminal cloverleaf structure. It has also been implicated in translational control of the 15-lipoxygenase mRNA, human papillomavirus type 16 L2 mRNA, and hepatitis A virus RNA. The encoded protein is also suggested to play a part in formation of a sequence-specific alpha-globin mRNP complex which is associated with alpha-globin mRNA stability. This multiexon structural mRNA is thought to be retrotransposed to generate PCBP-1, an intronless gene with functions similar to that of PCBP2. This gene and PCBP-1 have paralogous genes (PCBP3 and PCBP4) which are thought to have arisen as a result of duplication events of entire genes. This gene also has two processed pseudogenes (PCBP2P1 and PCBP2P2). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2018]

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=0.23981735).

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.2632T>C	p.Ser878Pro	missense	Exon 14 of 14	NP_001180440.1	Q12852-2
	MAP3K12	NM_006301.4		c.2533T>C	p.Ser845Pro	missense	Exon 15 of 15	NP_006292.3
	PCBP2	NM_031989.5	MANE Select	c.*1787A>G		downstream_gene	N/A	NP_114366.1	Q15366-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K12	ENST00000547488.6	TSL:2 MANE Select	c.2632T>C	p.Ser878Pro	missense	Exon 14 of 14	ENSP00000449038.1	Q12852-2
	MAP3K12	ENST00000267079.6	TSL:1	c.2533T>C	p.Ser845Pro	missense	Exon 15 of 15	ENSP00000267079.2	Q12852-1
	MAP3K12	ENST00000552365.1	TSL:1	n.*1362T>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000447889.1	F8VUG4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 2 AN: 1411162 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 702400

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30610

American (AMR) AF: 0.00 AC: 0 AN: 39250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24780

East Asian (EAS) AF: 0.00 AC: 0 AN: 35296

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79932

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085872

Other (OTH) AF: 0.00 AC: 0 AN: 57668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	Benign	0.18
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.0	B
Vest4		0.048
MutPred		0.12		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.68
MPC		0.32
ClinPred		0.73	D
GERP RS		1.1
Varity_R		0.21
gMVP		0.089
Mutation Taster		=66/34	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: chr12-53875013;