chr15-66484977-G-GTC
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP5BP7BA1
This summary comes from the ClinGen Evidence Repository: The c.694-8_694-7dupTC variant is an intronic variant located in intron 6 of the MAP2K1 gene. The filtering allele frequency in gnomAD v4.1.0 is 4.669% (3488/74934 alleles) in the African/African American population, which meets the threshold to apply BA1. The computational predictor SpliceAI predicts no impact on splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA147595/MONDO:0021060/045
Frequency
Consequence
NM_002755.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MAP2K1 | NM_002755.4 | c.694-8_694-7dupTC | splice_region_variant, intron_variant | Intron 6 of 10 | ENST00000307102.10 | NP_002746.1 | ||
MAP2K1 | NM_001411065.1 | c.550-8_550-7dupTC | splice_region_variant, intron_variant | Intron 5 of 9 | NP_001397994.1 | |||
MAP2K1 | XM_011521783.4 | c.628-8_628-7dupTC | splice_region_variant, intron_variant | Intron 6 of 10 | XP_011520085.1 | |||
MAP2K1 | XM_017022411.3 | c.616-8_616-7dupTC | splice_region_variant, intron_variant | Intron 5 of 9 | XP_016877900.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0130 AC: 1975AN: 152184Hom.: 37 Cov.: 32
GnomAD3 exomes AF: 0.00370 AC: 930AN: 251352Hom.: 14 AF XY: 0.00272 AC XY: 370AN XY: 135836
GnomAD4 exome AF: 0.00142 AC: 2064AN: 1458588Hom.: 44 Cov.: 31 AF XY: 0.00117 AC XY: 849AN XY: 725780
GnomAD4 genome AF: 0.0130 AC: 1977AN: 152302Hom.: 37 Cov.: 32 AF XY: 0.0124 AC XY: 921AN XY: 74470
ClinVar
Submissions by phenotype
not specified Benign:5
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694-8_694-7dupTC in intron 6 of MEK1: This variant (rs 113913469, no frequency i nformation) is not expected to have clinical significance because it has been id entified in as many as 0.94% (12/1275) probands including 11.8% (8/68) Black pro bands in our laboratory and is not located in the highly conserved region of the splicing consensus sequence. In addition, it has been identified in four other individuals with clinical features of Noonan spectrum disorders and another path ogenic variant tested by our laboratory. -
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. -
not provided Benign:3
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RASopathy Benign:2
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The c.694-8_694-7dupTC variant is an intronic variant located in intron 6 of the MAP2K1 gene. The filtering allele frequency in gnomAD v4.1.0 is 4.669% (3488/74934 alleles) in the African/African American population, which meets the threshold to apply BA1. The computational predictor SpliceAI predicts no impact on splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7 (Specification Version 2.1, 09/17/2024) -
Cardio-facio-cutaneous syndrome Benign:1
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Noonan syndrome Benign:1
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Noonan syndrome and Noonan-related syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at