NM_145160.3:c.448G>T

Variant names:

• chr15-67592942-G-T
• rs1220971652
• NM_145160.3:c.448G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_145160.3(MAP2K5):​c.448G>T​(p.Ala150Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,607,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MAP2K5 NM_145160.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.67
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27371377).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.448G>T	p.Ala150Ser	missense	Exon 7 of 22	NP_660143.1	Q13163-1
	MAP2K5	NM_002757.4		c.448G>T	p.Ala150Ser	missense	Exon 7 of 21	NP_002748.1	Q13163-2
	MAP2K5	NM_001206804.2		c.340G>T	p.Ala114Ser	missense	Exon 7 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.448G>T	p.Ala150Ser	missense	Exon 7 of 22	ENSP00000178640.5	Q13163-1
	MAP2K5	ENST00000395476.6	TSL:1	c.448G>T	p.Ala150Ser	missense	Exon 7 of 21	ENSP00000378859.2	Q13163-2
	MAP2K5	ENST00000952141.1		c.448G>T	p.Ala150Ser	missense	Exon 7 of 24	ENSP00000622200.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249564 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000880

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1455788 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724110

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

African (AFR) AF: 0.0000300 AC: 1 AN: 33312

American (AMR) AF: 0.0000677 AC: 3 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108186

Other (OTH) AF: 0.0000166 AC: 1 AN: 60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00192603), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.000328 AC: 5 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.20
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.82	P
Vest4		0.59
MutPred		0.28		Gain of phosphorylation at A150 (P = 0.0241)
MVP		0.82
MPC		0.23
ClinPred		0.31	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.26
Mutation Taster		=68/32	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: rs1220971652; hg19: chr15-67885280;