15-66479669-C-T

Variant names:

• chr15-66479669-C-T
• rs4255740
• NM_002755.4:c.569-2086C>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.569-2086C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 151,928 control chromosomes in the GnomAD database, including 6,504 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 0.28 (6504 hom., cov: 31)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.534
• Publications: 20 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.569-2086C>T		intron_variant	Intron 5 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.425-2086C>T		intron_variant	Intron 4 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.503-2086C>T		intron_variant	Intron 5 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.491-2086C>T		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.569-2086C>T		intron_variant	Intron 5 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42255 AN: 151808 Hom.: 6498 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.278 AC: 42284 AN: 151928 Hom.: 6504 Cov.: 31 AF XY: 0.279 AC XY: 20745 AN XY: 74236

African (AFR) AF: 0.148 AC: 6131 AN: 41458

American (AMR) AF: 0.327 AC: 4984 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3468

East Asian (EAS) AF: 0.315 AC: 1623 AN: 5148

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3127 AN: 10542

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22902 AN: 67920

Other (OTH) AF: 0.286 AC: 602 AN: 2106

Alfa AF: 0.314 Hom.: 6618

Bravo AF: 0.274

Asia WGS AF: 0.312 AC: 1089 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.92
DANN	Benign	0.68
PhyloP100		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4255740; hg19: chr15-66772007;