chr15-66436912-C-T

Variant names:

• chr15-66436912-C-T
• rs16949939
• NM_002755.4:c.438+20C>T

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.438+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,613,606 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.025 (628 hom.)
• Consequence: MAP2K1 NM_002755.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.191
• Publications: 8 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=-0.81).
• BP6: Variant 15-66436912-C-T is Benign according to our data. Variant chr15-66436912-C-T is described in ClinVar as Benign. ClinVar VariationId is 40749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0628 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.438+20C>T		intron	N/A	NP_002746.1
	MAP2K1	NM_001411065.1		c.372+20C>T		intron	N/A	NP_001397994.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.438+20C>T		intron	N/A	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.438+20C>T		intron	N/A	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.438+20C>T		intron	N/A	ENSP00000509308.1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2641 AN: 152174 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0251 AC: 6300 AN: 251342 AF XY: 0.0278

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.0119

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0247 AC: 36107 AN: 1461314 Hom.: 628 Cov.: 32 AF XY: 0.0260 AC XY: 18903 AN XY: 726974

African (AFR) AF: 0.00341 AC: 114 AN: 33470

American (AMR) AF: 0.0111 AC: 497 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 365 AN: 26126

East Asian (EAS) AF: 0.0209 AC: 828 AN: 39686

South Asian (SAS) AF: 0.0643 AC: 5542 AN: 86246

European-Finnish (FIN) AF: 0.0149 AC: 795 AN: 53276

Middle Eastern (MID) AF: 0.0354 AC: 204 AN: 5762

European-Non Finnish (NFE) AF: 0.0237 AC: 26364 AN: 1111662

Other (OTH) AF: 0.0232 AC: 1398 AN: 60372

GnomAD4 genome AF: 0.0174 AC: 2646 AN: 152292 Hom.: 37 Cov.: 32 AF XY: 0.0173 AC XY: 1290 AN XY: 74462

African (AFR) AF: 0.00438 AC: 182 AN: 41562

American (AMR) AF: 0.0132 AC: 202 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5180

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4830

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1671 AN: 68020

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0201 Hom.: 11

Bravo AF: 0.0163

Asia WGS AF: 0.0400 AC: 140 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiofaciocutaneous syndrome 3 (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.41
PhyloP100		0.19
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: rs16949939; hg19: chr15-66729250;