15-66485025-G-T

Position:

• chr15-66485025-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BS1_Supporting BS2

The ENST00000307102.10(MAP2K1):​c.729G>T​(p.Gln243His) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q243Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MAP2K1 ENST00000307102.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.22

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 51 pathogenic changes around while only 5 benign (91%) in ENST00000307102.10
• 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.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000616 (9/1461394) while in subpopulation AMR AF= 0.0000671 (3/44720). AF 95% confidence interval is 0.0000178. There are 0 homozygotes in gnomad4_exome. There are 5 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
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.729G>T	p.Gln243His	missense_variant	7/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.585G>T	p.Gln195His	missense_variant	6/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.663G>T	p.Gln221His	missense_variant	7/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.651G>T	p.Gln217His	missense_variant	6/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.729G>T	p.Gln243His	missense_variant	7/11	1	NM_002755.4	ENSP00000302486	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00000616 AC: 9 AN: 1461394 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2015

The p.Gln243His variant in MAP2K1 has been identified by our laboratory in 1 ind ividual with clinical features of Noonan syndrome and was inherited from an appa rently unaffected parent. It has not been identified in large population studie s. Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of the p.Gln243His variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 03, 2019

- -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2022

This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 228847). This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 243 of the MAP2K1 protein (p.Gln243His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.068	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.056	B;.
Vest4		0.70
MutPred		0.46		Gain of disorder (P = 0.1498);.;
MVP		0.97
MPC		1.3
ClinPred		0.56	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs772752167; hg19: chr15-66777363; COSMIC: COSV105880712; COSMIC: COSV105880712;