15-67806734-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145160.3(MAP2K5):c.1331A>G(p.Gln444Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,401,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAP2K5 NM_145160.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20753655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K5	NM_145160.3	c.1331A>G	p.Gln444Arg	missense_variant	22/22	ENST00000178640.10
MAP2K5	NM_002757.4	c.1301A>G	p.Gln434Arg	missense_variant	21/21
MAP2K5	NM_001206804.2	c.1223A>G	p.Gln408Arg	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K5	ENST00000178640.10	c.1331A>G	p.Gln444Arg	missense_variant	22/22	1	NM_145160.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401672 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692072

Gnomad4 AFR exome AF: 0.00

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: 9.24e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2022

The c.1331A>G (p.Q444R) 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 1331, causing the glutamine (Q) at amino acid position 444 to be replaced by an arginine (R). 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	0.079
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.69	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.037	B;B;.;B
Vest4		0.24
MutPred		0.26		Gain of MoRF binding (P = 0.0199);.;.;.;
MVP		0.78
MPC		1.1
ClinPred		0.52	D
GERP RS		5.5
Varity_R		0.057
gMVP		0.30

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: chr15-68099072;