rs1057519732

Positions:

• chr15-66436824-C-A
• chr15-66436824-C-G
• chr15-66436824-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The ENST00000307102.10(MAP2K1):​c.370C>A​(p.Pro124Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P124S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 ENST00000307102.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000307102.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-66436824-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375981.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.370C>A	p.Pro124Thr	missense_variant	3/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.304C>A	p.Pro102Thr	missense_variant	3/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.304C>A	p.Pro102Thr	missense_variant	3/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.370C>A	p.Pro124Thr	missense_variant	3/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.370C>A	p.Pro124Thr	missense_variant	3/11	1	NM_002755.4	ENSP00000302486	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it once in our laboratory de novo in a 5-year-old male with global delays, dysmorphism, short stature, failure to thrive, strabismus -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.85		Loss of catalytic residue at N122 (P = 0.0865);
MVP		0.96
MPC		2.6
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.77

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: rs1057519732; hg19: chr15-66729162;