chr15-67806697-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M432V) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145160.3. 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
	MAP2K5	NM_145160.3	MANE Select	c.1294A>C	p.Met432Leu	missense	Exon 22 of 22	NP_660143.1	Q13163-1
	MAP2K5	NM_002757.4		c.1264A>C	p.Met422Leu	missense	Exon 21 of 21	NP_002748.1	Q13163-2
	MAP2K5	NM_001206804.2		c.1186A>C	p.Met396Leu	missense	Exon 22 of 22	NP_001193733.1	Q13163-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K5	ENST00000178640.10	TSL:1 MANE Select	c.1294A>C	p.Met432Leu	missense	Exon 22 of 22	ENSP00000178640.5	Q13163-1
	MAP2K5	ENST00000395476.6	TSL:1	c.1264A>C	p.Met422Leu	missense	Exon 21 of 21	ENSP00000378859.2	Q13163-2
	MAP2K5	ENST00000952141.1		c.1465A>C	p.Met489Leu	missense	Exon 24 of 24	ENSP00000622200.1

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

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

African (AFR) AF: 0.0000316 AC: 1 AN: 31676

American (AMR) AF: 0.00 AC: 0 AN: 35866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25186

East Asian (EAS) AF: 0.00 AC: 0 AN: 35852

South Asian (SAS) AF: 0.00 AC: 0 AN: 79322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079666

Other (OTH) AF: 0.00 AC: 0 AN: 58060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00117289), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.36
Sift	Benign	0.10	T
Sift4G	Benign	0.36	T
Polyphen		0.41	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
Mutation Taster		=46/54	disease causing

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: rs2090816636; hg19: chr15-68099035;