chr15-66436839-T-C

Variant names:

• chr15-66436839-T-C
• rs1057519805
• NM_002755.4:c.385T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_002755.4(MAP2K1):​c.385T>C​(p.Phe129Leu) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90
• Publications: 30 publications found

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]

MAP2K1 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 15-66436839-T-C is Pathogenic according to our data. Variant chr15-66436839-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3775508.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. 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
	MAP2K1	NM_002755.4	MANE Select	c.385T>C	p.Phe129Leu	missense	Exon 3 of 11	NP_002746.1	Q02750-1
	MAP2K1	NM_001411065.1		c.319T>C	p.Phe107Leu	missense	Exon 3 of 10	NP_001397994.1	A0A8I5KYS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.385T>C	p.Phe129Leu	missense	Exon 3 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.385T>C	p.Phe129Leu	missense	Exon 3 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.385T>C	p.Phe129Leu	missense	Exon 3 of 12	ENSP00000509308.1	A0A8I5KRX5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiofaciocutaneous syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.45	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.64		Loss of loop (P = 0.2897)
MVP		0.88
MPC		2.6
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.77
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs1057519805; hg19: chr15-66729177; COSMIC: COSV61070231;