chr15-66404397-A-C

Variant names:

• chr15-66404397-A-C
• rs1549854
• NM_002755.4:c.80+16970A>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.80+16970A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 151,962 control chromosomes in the GnomAD database, including 15,563 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 0.44 (15563 hom., cov: 31)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349
• Publications: 16 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 = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.80+16970A>C		intron_variant	Intron 1 of 10	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.14+2450A>C		intron_variant	Intron 1 of 9		NP_001397994.1
MAP2K1	XM_011521783.4	c.14+2450A>C		intron_variant	Intron 1 of 10		XP_011520085.1
MAP2K1	XM_017022411.3	c.80+16970A>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.80+16970A>C		intron_variant	Intron 1 of 10	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67191 AN: 151844 Hom.: 15533 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.443 AC: 67269 AN: 151962 Hom.: 15563 Cov.: 31 AF XY: 0.444 AC XY: 32977 AN XY: 74258

African (AFR) AF: 0.338 AC: 14018 AN: 41458

American (AMR) AF: 0.525 AC: 8025 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3464

East Asian (EAS) AF: 0.449 AC: 2317 AN: 5160

South Asian (SAS) AF: 0.462 AC: 2226 AN: 4818

European-Finnish (FIN) AF: 0.456 AC: 4799 AN: 10534

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33234 AN: 67940

Other (OTH) AF: 0.440 AC: 927 AN: 2108

Alfa AF: 0.475 Hom.: 33605

Bravo AF: 0.444

Asia WGS AF: 0.430 AC: 1500 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	1.7
DANN	Benign	0.43
PhyloP100		-0.35
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: rs1549854; hg19: chr15-66696735;