rs8036023

Variant names:

• chr15-66438947-G-C
• rs8036023
• NM_002755.4:c.438+2055G>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.438+2055G>C 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 152,058 control chromosomes in the GnomAD database, including 7,571 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 (7571 hom., cov: 31)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.15
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.438+2055G>C		intron_variant	Intron 3 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.372+2055G>C		intron_variant	Intron 3 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.372+2055G>C		intron_variant	Intron 3 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.438+2055G>C		intron_variant	Intron 3 of 9		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.438+2055G>C		intron_variant	Intron 3 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46479 AN: 151940 Hom.: 7560 Cov.: 31

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.310

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

GnomAD4 genome AF: 0.306 AC: 46525 AN: 152058 Hom.: 7571 Cov.: 31 AF XY: 0.309 AC XY: 22948 AN XY: 74298

African (AFR) AF: 0.210 AC: 8724 AN: 41516

American (AMR) AF: 0.392 AC: 5978 AN: 15260

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

East Asian (EAS) AF: 0.373 AC: 1925 AN: 5166

South Asian (SAS) AF: 0.373 AC: 1795 AN: 4814

European-Finnish (FIN) AF: 0.309 AC: 3263 AN: 10564

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

European-Non Finnish (NFE) AF: 0.339 AC: 23027 AN: 67958

Other (OTH) AF: 0.312 AC: 658 AN: 2110

Alfa AF: 0.302 Hom.: 933

Bravo AF: 0.307

Asia WGS AF: 0.344 AC: 1199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.041
DANN	Benign	0.50
PhyloP100		-2.1
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: rs8036023; hg19: chr15-66731285;