chr15-66435259-G-C

Variant names:

• chr15-66435259-G-C
• rs16949924
• NM_002755.4:c.291+22G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002755.4(MAP2K1):​c.291+22G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,596,254 control chromosomes in the GnomAD database, including 91,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6512 hom., cov: 31)
  • Exomes 𝑓: 0.34 (84717 hom.)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 0.115
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-66435259-G-C is Benign according to our data. Variant chr15-66435259-G-C is described in ClinVar as Benign. ClinVar VariationId is 40784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.353 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.291+22G>C		intron	N/A	NP_002746.1
	MAP2K1	NM_001411065.1		c.225+22G>C		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.291+22G>C		intron	N/A	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.291+22G>C		intron	N/A	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.291+22G>C		intron	N/A	ENSP00000509308.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42103 AN: 151780 Hom.: 6506 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.319 AC: 80030 AN: 250750 AF XY: 0.324

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.338 AC: 488843 AN: 1444356 Hom.: 84717 Cov.: 28 AF XY: 0.339 AC XY: 243956 AN XY: 719736

African (AFR) AF: 0.136 AC: 4497 AN: 33128

American (AMR) AF: 0.349 AC: 15590 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6183 AN: 25954

East Asian (EAS) AF: 0.296 AC: 11717 AN: 39596

South Asian (SAS) AF: 0.371 AC: 31848 AN: 85910

European-Finnish (FIN) AF: 0.303 AC: 16151 AN: 53390

Middle Eastern (MID) AF: 0.252 AC: 1449 AN: 5740

European-Non Finnish (NFE) AF: 0.349 AC: 382422 AN: 1096140

Other (OTH) AF: 0.318 AC: 18986 AN: 59792

GnomAD4 genome AF: 0.277 AC: 42130 AN: 151898 Hom.: 6512 Cov.: 31 AF XY: 0.278 AC XY: 20657 AN XY: 74222

African (AFR) AF: 0.142 AC: 5902 AN: 41468

American (AMR) AF: 0.325 AC: 4964 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 824 AN: 3418

East Asian (EAS) AF: 0.314 AC: 1620 AN: 5162

South Asian (SAS) AF: 0.368 AC: 1768 AN: 4808

European-Finnish (FIN) AF: 0.297 AC: 3133 AN: 10532

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22985 AN: 67946

Other (OTH) AF: 0.289 AC: 609 AN: 2108

Alfa AF: 0.285 Hom.: 1230

Bravo AF: 0.272

Asia WGS AF: 0.310 AC: 1080 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Squamous cell lung carcinoma Uncertain:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vivo

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiofaciocutaneous syndrome 3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.70
PhyloP100		0.12
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: rs16949924; hg19: chr15-66727597; COSMIC: COSV61070911;