rs750750577

Variant names:

• chr12-53482816-C-T
• rs750750577
• NM_001193511.2:c.1987G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001193511.2(MAP3K12):​c.1987G>A​(p.Gly663Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MAP3K12 NM_001193511.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062476188).
• BS2: High AC in GnomAdExome4 at 8 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.1987G>A	p.Gly663Arg	missense	Exon 11 of 14	NP_001180440.1	Q12852-2
	MAP3K12	NM_006301.4		c.1888G>A	p.Gly630Arg	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.1987G>A	p.Gly663Arg	missense	Exon 11 of 14	ENSP00000449038.1	Q12852-2
	MAP3K12	ENST00000267079.6	TSL:1	c.1888G>A	p.Gly630Arg	missense	Exon 12 of 15	ENSP00000267079.2	Q12852-1
	MAP3K12	ENST00000552365.1	TSL:1	n.*717G>A		non_coding_transcript_exon	Exon 11 of 14	ENSP00000447889.1	F8VUG4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247028 AF XY: 0.0000298

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458742 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725298

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110066

Other (OTH) AF: 0.0000166 AC: 1 AN: 60212

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.29
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.090
Sift	Benign	0.21	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.30		Gain of catalytic residue at P635 (P = 5e-04)
MVP		0.33
MPC		0.19
ClinPred		0.062	T
GERP RS		3.2
Varity_R		0.082
gMVP		0.25
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs750750577; hg19: chr12-53876600;