NM_002446.4:c.56C>G

Variant names:

• chr19-40192087-C-G
• rs1226481460
• NM_002446.4:c.56C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_002446.4(MAP3K10):​c.56C>G​(p.Pro19Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000366 in 1,367,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: MAP3K10 NM_002446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62
• Publications: 0 publications found

Genes affected

MAP3K10 (HGNC:6849): (mitogen-activated protein kinase kinase kinase 10) The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase has been shown to activate MAPK8/JNK and MKK4/SEK1, and this kinase itself can be phoshorylated, and thus activated by JNK kinases. This kinase functions preferentially on the JNK signaling pathway, and is reported to be involved in nerve growth factor (NGF) induced neuronal apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38108283).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002446.4. 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
	MAP3K10	NM_002446.4	MANE Select	c.56C>G	p.Pro19Arg	missense	Exon 1 of 10	NP_002437.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K10	ENST00000253055.8	TSL:1 MANE Select	c.56C>G	p.Pro19Arg	missense	Exon 1 of 10	ENSP00000253055.2	Q02779
	MAP3K10	ENST00000856942.1		c.56C>G	p.Pro19Arg	missense	Exon 1 of 10	ENSP00000527002.1
	MAP3K10	ENST00000941194.1		c.56C>G	p.Pro19Arg	missense	Exon 1 of 10	ENSP00000611253.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000366 AC: 5 AN: 1367500 Hom.: 0 Cov.: 33 AF XY: 0.00000446 AC XY: 3 AN XY: 672186

African (AFR) AF: 0.00 AC: 0 AN: 30088

American (AMR) AF: 0.00 AC: 0 AN: 29792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21436

East Asian (EAS) AF: 0.00 AC: 0 AN: 36212

South Asian (SAS) AF: 0.00 AC: 0 AN: 72680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1069632

Other (OTH) AF: 0.00 AC: 0 AN: 56764

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.72	P
Vest4		0.40
MutPred		0.54		Gain of MoRF binding (P = 0.0174)
MVP		0.45
MPC		1.5
ClinPred		0.94	D
GERP RS		2.1
Varity_R		0.66
gMVP		0.42
Mutation Taster		=76/24	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

dbSNP: rs1226481460; hg19: chr19-40697994;