15-66468004-A-G

Variant names:

• chr15-66468004-A-G
• rs8039880
• NM_002755.4:c.569-13751A>G

Variant summary

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

The NM_002755.4(MAP2K1):​c.569-13751A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,248 control chromosomes in the GnomAD database, including 3,448 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 0.21 (3448 hom., cov: 33)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.198
• 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=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.569-13751A>G		intron_variant	Intron 5 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.425-13751A>G		intron_variant	Intron 4 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.503-13751A>G		intron_variant	Intron 5 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.491-13751A>G		intron_variant	Intron 4 of 9		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.569-13751A>G		intron_variant	Intron 5 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31938 AN: 152130 Hom.: 3443 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.210 AC: 31964 AN: 152248 Hom.: 3448 Cov.: 33 AF XY: 0.211 AC XY: 15678 AN XY: 74438

African (AFR) AF: 0.235 AC: 9758 AN: 41548

American (AMR) AF: 0.215 AC: 3297 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3468

East Asian (EAS) AF: 0.378 AC: 1956 AN: 5174

South Asian (SAS) AF: 0.197 AC: 949 AN: 4828

European-Finnish (FIN) AF: 0.204 AC: 2162 AN: 10598

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12300 AN: 68012

Other (OTH) AF: 0.215 AC: 454 AN: 2114

Alfa AF: 0.189 Hom.: 5812

Bravo AF: 0.216

Asia WGS AF: 0.268 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.20
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: rs8039880; hg19: chr15-66760342;