rs16949924

Positions:

• chr15-66435259-G-C
• chr15-66435259-G-T

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.115

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.291+22G>C		intron_variant		ENST00000307102.10
MAP2K1	NM_001411065.1	c.225+22G>C		intron_variant
MAP2K1	XM_011521783.4	c.225+22G>C		intron_variant
MAP2K1	XM_017022411.3	c.291+22G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.291+22G>C		intron_variant		1	NM_002755.4	P1

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

GnomAD3 exomes AF: 0.319 AC: 80030 AN: 250750 Hom.: 13235 AF XY: 0.324 AC XY: 43972 AN XY: 135584

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 SAS exome AF: 0.370

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

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.318

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

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.338

Gnomad4 OTH AF: 0.289

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Squamous cell lung carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cardiofaciocutaneous syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs16949924; hg19: chr15-66727597; COSMIC: COSV61070911;