chr15-67806697-A-G

Variant names:

• chr15-67806697-A-G
• rs2090816636
• NM_145160.3:c.1294A>G

Variant summary

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

The NM_145160.3(MAP2K5):​c.1294A>G​(p.Met432Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAP2K5 NM_145160.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>G	p.Met432Val	missense_variant	Exon 22 of 22	ENST00000178640.10	NP_660143.1
MAP2K5	NM_002757.4	c.1264A>G	p.Met422Val	missense_variant	Exon 21 of 21		NP_002748.1
MAP2K5	NM_001206804.2	c.1186A>G	p.Met396Val	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>G	p.Met432Val	missense_variant	Exon 22 of 22	1	NM_145160.3	ENSP00000178640.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399650 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690506

Gnomad4 AFR exome AF: 0.0000631

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000374 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1294A>G (p.M432V) alteration is located in exon 22 (coding exon 22) of the MAP2K5 gene. This alteration results from a A to G substitution at nucleotide position 1294, causing the methionine (M) at amino acid position 432 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.3	L;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.094	T;D;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.61	P;P;.;B
Vest4		0.87
MVP		0.76
MPC		1.1
ClinPred		0.72	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs2090816636; hg19: chr15-68099035;