15-67692480-C-G

Variant names:

• chr15-67692480-C-G
• rs55966838
• NM_145160.3:c.849C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_145160.3(MAP2K5):​c.849C>G​(p.Asp283Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D283D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAP2K5 NM_145160.3 missense, splice_region
• Scores: Splicing: ADA: 0.00003125
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

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.849C>G	p.Asp283Glu	missense splice_region	Exon 14 of 22	NP_660143.1	Q13163-1
	MAP2K5	NM_002757.4		c.849C>G	p.Asp283Glu	missense splice_region	Exon 14 of 21	NP_002748.1	Q13163-2
	MAP2K5	NM_001206804.2		c.741C>G	p.Asp247Glu	missense splice_region	Exon 14 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.849C>G	p.Asp283Glu	missense splice_region	Exon 14 of 22	ENSP00000178640.5	Q13163-1
	MAP2K5	ENST00000395476.6	TSL:1	c.849C>G	p.Asp283Glu	missense splice_region	Exon 14 of 21	ENSP00000378859.2	Q13163-2
	MAP2K5	ENST00000952141.1		c.849C>G	p.Asp283Glu	missense splice_region	Exon 14 of 24	ENSP00000622200.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460472 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726638

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110952

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 23

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		0.24
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.97		Gain of methylation at K285 (P = 0.0766)
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		1.1
Varity_R		0.74
gMVP		0.92
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.14		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: rs55966838; hg19: chr15-67984818;