chr15-66387358-A-G

Position:

• chr15-66387358-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_002755.4(MAP2K1):​c.11A>G​(p.Lys4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K4K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.52

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAP2K1. . Gene score misZ 3.1085 (greater than the threshold 3.09). Trascript score misZ 3.7499 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18643251).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000283 (4/1411230) while in subpopulation AMR AF= 0.0000805 (3/37272). AF 95% confidence interval is 0.0000213. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.11A>G	p.Lys4Arg	missense_variant	1/11	ENST00000307102.10
MAP2K1	XM_017022411.3	c.11A>G	p.Lys4Arg	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.11A>G	p.Lys4Arg	missense_variant	1/11	1	NM_002755.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000116 AC: 2 AN: 172566 Hom.: 0 AF XY: 0.0000218 AC XY: 2 AN XY: 91804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1411230 Hom.: 0 Cov.: 32 AF XY: 0.00000574 AC XY: 4 AN XY: 697246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000805

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000258 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 27, 2017

Variant summary: The c.11A>G (p.Lys4Arg) in MAP2K1 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain and no functional studies implying the impact of this varian ton protein function have been published at the time of evaluation. The variant is absent from the control population dataset of ExAC (0/ 21980 chrs tested). Small numbers of sample in ExAC database indicate a low coverage site, therefore this data should be reviewed with caution. The variant is present in control population of gnomAD at a frequency of 0.00001208 (2/ 165522 chrs tested), which exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000025). The presence of the variant in presumably unaffected individual in gnomAD suggests a benign outcome, as mutations in MAP2K1 are extremely rare in hematologic malignancy (COSMIC). The variant has not, to our knowledge, been reported in affected individuals via published reports or by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more evidence becomes available. -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP2K1 protein function. ClinVar contains an entry for this variant (Variation ID: 496174). This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. This variant is present in population databases (rs761150136, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4 of the MAP2K1 protein (p.Lys4Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	-0.41	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.37
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.33		Loss of methylation at K4 (P = 0.0097);
MVP		0.76
MPC		1.1
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.19
gMVP		0.29

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: rs761150136; hg19: chr15-66679696;