chr15-66436742-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002755.4(MAP2K1):​c.292-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAP2K1
NM_002755.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0006752
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.683

Publications

0 publications found
Variant links:
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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K1NM_002755.4 linkc.292-4C>T splice_region_variant, intron_variant Intron 2 of 10 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9
MAP2K1NM_001411065.1 linkc.226-4C>T splice_region_variant, intron_variant Intron 2 of 9 NP_001397994.1
MAP2K1XM_011521783.4 linkc.226-4C>T splice_region_variant, intron_variant Intron 2 of 10 XP_011520085.1 B4DFY5
MAP2K1XM_017022411.3 linkc.292-4C>T splice_region_variant, intron_variant Intron 2 of 9 XP_016877900.1 Q02750-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.292-4C>T splice_region_variant, intron_variant Intron 2 of 10 1 NM_002755.4 ENSP00000302486.5 Q02750-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461774
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727194
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111926
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
CADD
Benign
5.9
DANN
Benign
0.72
PhyloP100
-0.68

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00068
dbscSNV1_RF
Benign
0.054
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

Other links and lift over

dbSNP: rs771407622; hg19: chr15-66729080; API