chr15-66436824-C-T

Variant names:

• chr15-66436824-C-T
• rs1057519732
• NM_002755.4:c.370C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP3 PP2 PS2 PM2 PM1 PS3

This summary comes from the ClinGen Evidence Repository: The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID:22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PM1, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602456/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1 O:2
• Conservation: PhyloP100: 7.79
• Publications: 81 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: Pathogenic. The variant received 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.370C>T	p.Pro124Ser	missense	Exon 3 of 11	NP_002746.1	Q02750-1
	MAP2K1	NM_001411065.1		c.304C>T	p.Pro102Ser	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.370C>T	p.Pro124Ser	missense	Exon 3 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.370C>T	p.Pro124Ser	missense	Exon 3 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.370C>T	p.Pro124Ser	missense	Exon 3 of 12	ENSP00000509308.1	A0A8I5KRX5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	RASopathy (2)
1	-	-	Cardiofaciocutaneous syndrome 3 (1)
1	-	-	Noonan syndrome (1)
1	-	-	not provided (1)
-	-	-	Metastatic melanoma (1)
-	-	-	Spitz Melanocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.83		Loss of stability (P = 0.0746)
MVP		0.82
MPC		2.4
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.77
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519732; hg19: chr15-66729162; COSMIC: COSV61068297;