rs397516791

Variant names:

• chr15-66435221-T-G
• rs397516791
• NM_002755.4:c.275T>G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PM6 PP3 PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (PP3). The 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). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, PMID:35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134601/MONDO:0015280/045

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.90
• Publications: 2 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 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.275T>G	p.Leu92Arg	missense	Exon 2 of 11	NP_002746.1	Q02750-1
	MAP2K1	NM_001411065.1		c.209T>G	p.Leu70Arg	missense	Exon 2 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.275T>G	p.Leu92Arg	missense	Exon 2 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.275T>G	p.Leu92Arg	missense	Exon 2 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.275T>G	p.Leu92Arg	missense	Exon 2 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
2	-	-	Cardio-facio-cutaneous syndrome (2)
-	1	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	not provided (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	-0.29	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.047	D
Polyphen		0.73	P
Vest4		0.80
MutPred		0.40		Gain of MoRF binding (P = 0.0045)
MVP		0.99
MPC		2.7
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.84
Mutation Taster		=30/70	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: rs397516791; hg19: chr15-66727559;