rs4489951

Variant names:

• chr15-66418556-G-A
• rs4489951
• NM_002755.4:c.81-16471G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-66418556-G-A
• chr15-66418556-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002755.4(MAP2K1):​c.81-16471G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 152,174 control chromosomes in the GnomAD database, including 55,776 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (55776 hom., cov: 33)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810
• Publications: 11 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: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.81-16471G>A		intron	N/A	NP_002746.1
	MAP2K1	NM_001411065.1		c.15-16471G>A		intron	N/A	NP_001397994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.81-16471G>A		intron	N/A	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.81-16471G>A		intron	N/A	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.81-16471G>A		intron	N/A	ENSP00000509308.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128701 AN: 152056 Hom.: 55736 Cov.: 33

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.919

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.864

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.846 AC: 128797 AN: 152174 Hom.: 55776 Cov.: 33 AF XY: 0.850 AC XY: 63263 AN XY: 74410

African (AFR) AF: 0.640 AC: 26531 AN: 41436

American (AMR) AF: 0.919 AC: 14065 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3130 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5187 AN: 5190

South Asian (SAS) AF: 0.970 AC: 4681 AN: 4828

European-Finnish (FIN) AF: 0.919 AC: 9750 AN: 10608

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.920 AC: 62543 AN: 68016

Other (OTH) AF: 0.865 AC: 1826 AN: 2112

Alfa AF: 0.911 Hom.: 51573

Bravo AF: 0.837

Asia WGS AF: 0.951 AC: 3304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.34
DANN	Benign	0.42
PhyloP100		-0.081
Mutation Taster		=100/0	polymorphism (auto)

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: rs4489951; hg19: chr15-66710894;