rs397516794

Variant names:

• chr15-66485171-C-A
• NM_002755.4:c.875C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-66485171-C-A
• chr15-66485171-C-G
• chr15-66485171-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_002755.4(MAP2K1):​c.875C>A​(p.Thr292Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T292I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by MAPK1 (size 0) in uniprot entity MP2K1_HUMAN
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18281054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.875C>A	p.Thr292Asn	missense_variant	Exon 7 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.731C>A	p.Thr244Asn	missense_variant	Exon 6 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.809C>A	p.Thr270Asn	missense_variant	Exon 7 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.797C>A	p.Thr266Asn	missense_variant	Exon 6 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.875C>A	p.Thr292Asn	missense_variant	Exon 7 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461542 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	0.45	N;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.23	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.22	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;.
Vest4		0.26
MutPred		0.30		Loss of phosphorylation at T292 (P = 5e-04);.;
MVP		0.64
MPC		1.4
ClinPred		0.72	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-66777509;