15-67806697-A-C

Variant names:

• chr15-67806697-A-C
• NM_145160.3:c.1294A>C

Variant summary

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

The NM_145160.3(MAP2K5):​c.1294A>C​(p.Met432Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,650 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: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MAP2K5 NM_145160.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

Genes affected

MAP2K5 (HGNC:6845): (mitogen-activated protein kinase kinase 5) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been described. [provided by RefSeq, May 2011]

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
MAP2K5	NM_145160.3	c.1294A>C	p.Met432Leu	missense_variant	Exon 22 of 22	ENST00000178640.10	NP_660143.1
MAP2K5	NM_002757.4	c.1264A>C	p.Met422Leu	missense_variant	Exon 21 of 21		NP_002748.1
MAP2K5	NM_001206804.2	c.1186A>C	p.Met396Leu	missense_variant	Exon 22 of 22		NP_001193733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K5	ENST00000178640.10	c.1294A>C	p.Met432Leu	missense_variant	Exon 22 of 22	1	NM_145160.3	ENSP00000178640.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399650 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690506

Gnomad4 AFR exome AF: 0.0000316

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.93	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.10	T;D;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.41	B;P;.;B
Vest4		0.69
MutPred		0.51		Loss of catalytic residue at M432 (P = 0.0353);.;.;.;
MVP		0.76
MPC		0.99
ClinPred		0.71	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.33

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: chr15-68099035;