chr19-4097282-G-A
Variant summary
Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_030662.4(MAP2K2):c.981C>T(p.Asn327Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,608,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_030662.4 synonymous
Scores
Clinical Significance
Conservation
Publications
- cardiofaciocutaneous syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- cardiofaciocutaneous syndrome 4Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Noonan syndromeInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.981C>T | p.Asn327Asn | synonymous_variant | Exon 8 of 11 | ENST00000262948.10 | NP_109587.1 | |
MAP2K2 | NM_001440689.1 | c.411C>T | p.Asn137Asn | synonymous_variant | Exon 6 of 9 | NP_001427618.1 | ||
MAP2K2 | NM_001440688.1 | c.706-1833C>T | intron_variant | Intron 6 of 8 | NP_001427617.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000119 AC: 18AN: 151156Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000116 AC: 29AN: 250462 AF XY: 0.0000886 show subpopulations
GnomAD4 exome AF: 0.000221 AC: 322AN: 1457476Hom.: 0 Cov.: 32 AF XY: 0.000218 AC XY: 158AN XY: 725040 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000119 AC: 18AN: 151268Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 11AN XY: 73876 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:3
MAP2K2: BP4, BP7 -
- -
Variant summary: The MAP2K2 c.981C>T (p.Asn327Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 14/119582 control chromosomes at a frequency of 0.0001171, which is approximately 47 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
not specified Benign:1
Asn327Asn in exon 8 of MEK2: This variant is not expected to have clinical or pa thological significance because it does not alter an amino acid residue and is n ot located near a splice junction. This variant has been identified in 2/732 (0. 2%) of Caucasian probands tested by our laboratory; one of those individuals als o had a pathogenic RAF1 variant. -
MAP2K2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at