NM_002755.4:c.-31dupC

Variant names:

• chr15-66387311-T-TC
• rs730880340
• NM_002755.4:c.-31dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002755.4(MAP2K1):​c.-31dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 1,516,248 control chromosomes in the GnomAD database, including 8,983 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (977 hom., cov: 31)
  • Exomes 𝑓: 0.095 (8006 hom.)
• Consequence: MAP2K1 NM_002755.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.965
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 15-66387311-T-TC is Benign according to our data. Variant chr15-66387311-T-TC is described in ClinVar as Benign. ClinVar VariationId is 40710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.324 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.-31dupC		5_prime_UTR	Exon 1 of 11	NP_002746.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.-31dupC		5_prime_UTR	Exon 1 of 11	ENSP00000302486.5
	MAP2K1	ENST00000425818.2	TSL:5	n.481dupC		non_coding_transcript_exon	Exon 1 of 5
	MAP2K1	ENST00000687191.1		n.406dupC		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15489 AN: 151718 Hom.: 978 Cov.: 31

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0818

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.119 AC: 18384 AN: 154242 AF XY: 0.116

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.0807

Gnomad NFE exome AF: 0.0832

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.0947 AC: 129233 AN: 1364416 Hom.: 8006 Cov.: 27 AF XY: 0.0947 AC XY: 63904 AN XY: 675044

African (AFR) AF: 0.0910 AC: 2813 AN: 30898

American (AMR) AF: 0.156 AC: 5573 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3216 AN: 24886

East Asian (EAS) AF: 0.369 AC: 13097 AN: 35512

South Asian (SAS) AF: 0.0964 AC: 7575 AN: 78562

European-Finnish (FIN) AF: 0.0832 AC: 4073 AN: 48968

Middle Eastern (MID) AF: 0.0991 AC: 544 AN: 5490

European-Non Finnish (NFE) AF: 0.0824 AC: 86282 AN: 1047686

Other (OTH) AF: 0.107 AC: 6060 AN: 56750

GnomAD4 genome AF: 0.102 AC: 15484 AN: 151832 Hom.: 977 Cov.: 31 AF XY: 0.103 AC XY: 7636 AN XY: 74170

African (AFR) AF: 0.0938 AC: 3887 AN: 41440

American (AMR) AF: 0.133 AC: 2026 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3472

East Asian (EAS) AF: 0.337 AC: 1721 AN: 5102

South Asian (SAS) AF: 0.111 AC: 533 AN: 4810

European-Finnish (FIN) AF: 0.0818 AC: 862 AN: 10542

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0836 AC: 5679 AN: 67898

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.0935 Hom.: 136

Bravo AF: 0.108

Asia WGS AF: 0.205 AC: 709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 15, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 07, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=300/0	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: rs730880340; hg19: chr15-66679649; COSMIC: COSV61072417; COSMIC: COSV61072417;