chr15-66387358-A-G

Variant names:

• chr15-66387358-A-G
• rs761150136
• NM_002755.4:c.11A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002755.4(MAP2K1):​c.11A>G​(p.Lys4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K4K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.52
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18643251).

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.11A>G	p.Lys4Arg	missense	Exon 1 of 11	NP_002746.1	Q02750-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.11A>G	p.Lys4Arg	missense	Exon 1 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.11A>G	p.Lys4Arg	missense	Exon 1 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.11A>G	p.Lys4Arg	missense	Exon 1 of 12	ENSP00000509308.1	A0A8I5KRX5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 172566 AF XY: 0.0000218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000283 AC: 4 AN: 1411230 Hom.: 0 Cov.: 32 AF XY: 0.00000574 AC XY: 4 AN XY: 697246

African (AFR) AF: 0.00 AC: 0 AN: 32342

American (AMR) AF: 0.0000805 AC: 3 AN: 37272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 37052

South Asian (SAS) AF: 0.00 AC: 0 AN: 80164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085286

Other (OTH) AF: 0.00 AC: 0 AN: 58388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000258 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	-0.41	N
PhyloP100		4.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.37
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.33		Loss of methylation at K4 (P = 0.0097)
MVP		0.76
MPC		1.1
ClinPred		0.18	T
GERP RS		4.0
PromoterAI		0.060	Neutral
Varity_R		0.19
gMVP		0.29
Mutation Taster		=89/11	polymorphism

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: rs761150136; hg19: chr15-66679696;