15-66436762-T-G

Variant names:

• chr15-66436762-T-G
• rs730880502
• NM_002755.4:c.308T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_002755.4(MAP2K1):​c.308T>G​(p.Ile103Ser) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MAP2K1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 3.1085 (above the threshold of 3.09). Trascript score misZ: 3.7499 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.308T>G	p.Ile103Ser	missense_variant	Exon 3 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.242T>G	p.Ile81Ser	missense_variant	Exon 3 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.242T>G	p.Ile81Ser	missense_variant	Exon 3 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.308T>G	p.Ile103Ser	missense_variant	Exon 3 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.308T>G	p.Ile103Ser	missense_variant	Exon 3 of 11	1	NM_002755.4	ENSP00000302486.5

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

not provided Uncertain:1

Jul 19, 2012

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I103S missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. I103S is considered a non-conservative amino acid substitution as a non-polar isoleucine residue is replaced with a polar Serine residue. Additionally, the NHLBI ESP Exome Variant Server reports I103S was not observed in approximately 6000 control samples from individuals of European and African American backgrounds indicating it is not a common benign variant in these populations. However, I103S occurs at a position that is not highly conserved in this protein or across species. Therefore, this result cannot be interpreted for diagnosis or used for genetic counseling without further studies. The variant is found in NOONAN panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.83	L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Polyphen		0.37	B
Vest4		0.83
MutPred		0.40		Gain of disorder (P = 0.0101);
MVP		0.97
MPC		2.8
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.90

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: rs730880502; hg19: chr15-66729100; COSMIC: COSV104596910;