15-66455571-G-T

Variant names:

• chr15-66455571-G-T
• rs7181936
• NM_002755.4:c.568+10864G>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.568+10864G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,052 control chromosomes in the GnomAD database, including 7,566 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 0.31 (7566 hom., cov: 32)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.546
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 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.568+10864G>T		intron	N/A	NP_002746.1
	MAP2K1	NM_001411065.1		c.424+10864G>T		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.568+10864G>T		intron	N/A	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.568+10864G>T		intron	N/A	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.569-3135G>T		intron	N/A	ENSP00000509308.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46473 AN: 151934 Hom.: 7555 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.306 AC: 46520 AN: 152052 Hom.: 7566 Cov.: 32 AF XY: 0.309 AC XY: 22950 AN XY: 74298

African (AFR) AF: 0.210 AC: 8711 AN: 41516

American (AMR) AF: 0.392 AC: 5990 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 829 AN: 3466

East Asian (EAS) AF: 0.376 AC: 1944 AN: 5164

South Asian (SAS) AF: 0.374 AC: 1802 AN: 4818

European-Finnish (FIN) AF: 0.308 AC: 3250 AN: 10566

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23017 AN: 67936

Other (OTH) AF: 0.309 AC: 651 AN: 2104

Alfa AF: 0.324 Hom.: 2680

Bravo AF: 0.307

Asia WGS AF: 0.345 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.86
DANN	Benign	0.77
PhyloP100		-0.55
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: rs7181936; hg19: chr15-66747909;