chr15-66426931-T-C

Variant names:

• chr15-66426931-T-C
• rs1432442
• NM_002755.4:c.81-8096T>C

Variant summary

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

The NM_002755.4(MAP2K1):​c.81-8096T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 152,188 control chromosomes in the GnomAD database, including 58,653 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 0.88 (58653 hom., cov: 33)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530
• Publications: 19 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.81-8096T>C		intron_variant	Intron 1 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.15-8096T>C		intron_variant	Intron 1 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.15-8096T>C		intron_variant	Intron 1 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.81-8096T>C		intron_variant	Intron 1 of 9		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.81-8096T>C		intron_variant	Intron 1 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133203 AN: 152070 Hom.: 58592 Cov.: 33

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.870

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

GnomAD4 genome AF: 0.876 AC: 133323 AN: 152188 Hom.: 58653 Cov.: 33 AF XY: 0.876 AC XY: 65157 AN XY: 74406

African (AFR) AF: 0.831 AC: 34469 AN: 41496

American (AMR) AF: 0.860 AC: 13151 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3013 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3400 AN: 5168

South Asian (SAS) AF: 0.889 AC: 4285 AN: 4822

European-Finnish (FIN) AF: 0.918 AC: 9731 AN: 10598

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.916 AC: 62306 AN: 68014

Other (OTH) AF: 0.870 AC: 1840 AN: 2114

Alfa AF: 0.902 Hom.: 101852

Bravo AF: 0.866

Asia WGS AF: 0.790 AC: 2749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	7.9
DANN	Benign	0.62
PhyloP100		0.053
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: rs1432442; hg19: chr15-66719269; COSMIC: COSV107397002;