15-66387236-G-GGGCCCGC

Variant names:

• chr15-66387236-G-GGGCCCGC
• rs575854200
• NM_002755.4:c.-105_-99dupCGGCCCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002755.4(MAP2K1):​c.-105_-99dupCGGCCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 867,502 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: MAP2K1 NM_002755.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 15-66387236-G-GGGCCCGC is Benign according to our data. Variant chr15-66387236-G-GGGCCCGC is described in ClinVar as [Likely_benign]. Clinvar id is 1189560.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00344 (523/152218) while in subpopulation AFR AF = 0.0121 (501/41540). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.-105_-99dupCGGCCCG		5_prime_UTR_variant	Exon 1 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	XM_017022411.3	c.-105_-99dupCGGCCCG		5_prime_UTR_variant	Exon 1 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.-105_-99dupCGGCCCG		5_prime_UTR_variant	Exon 1 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152108 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000268 AC: 192 AN: 715284 Hom.: 2 Cov.: 9 AF XY: 0.000235 AC XY: 86 AN XY: 366080

African (AFR) AF: 0.0101 AC: 148 AN: 14618

American (AMR) AF: 0.000453 AC: 9 AN: 19856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15526

East Asian (EAS) AF: 0.00 AC: 0 AN: 28744

South Asian (SAS) AF: 0.0000759 AC: 4 AN: 52722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2614

European-Non Finnish (NFE) AF: 0.00000796 AC: 4 AN: 502324

Other (OTH) AF: 0.000793 AC: 27 AN: 34060

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152218 Hom.: 3 Cov.: 33 AF XY: 0.00347 AC XY: 258 AN XY: 74412

African (AFR) AF: 0.0121 AC: 501 AN: 41540

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00379 Hom.: 0

Bravo AF: 0.00388

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs575854200; hg19: chr15-66679574;