NM_024596.5:c.2145G>A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_024596.5(MCPH1):c.2145G>A(p.Trp715*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000221 in 1,613,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024596.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MCPH1 | ENST00000344683.10 | c.2145G>A | p.Trp715* | stop_gained | Exon 12 of 14 | 1 | NM_024596.5 | ENSP00000342924.5 | ||
ANGPT2 | ENST00000629816 | c.*3241C>T | 3_prime_UTR_variant | Exon 9 of 9 | 1 | NM_001118887.2 | ENSP00000486858.2 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152150Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000112 AC: 28AN: 249568Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135402
GnomAD4 exome AF: 0.000230 AC: 336AN: 1460870Hom.: 0 Cov.: 30 AF XY: 0.000213 AC XY: 155AN XY: 726758
GnomAD4 genome AF: 0.000131 AC: 20AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74322
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
This sequence change creates a premature translational stop signal (p.Trp715*) in the MCPH1 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs201599657, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with MCPH1-related conditions (PMID: 34670123). ClinVar contains an entry for this variant (Variation ID: 285523). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Identified in a patient with transposition of great arteries and others with unspecified cardiovascular disease in published literature, though no individuals were reported to have non-cardiological features (PMID: 31345219; PMID: 34670123); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34670123, 34759951, 31345219) -
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Microcephaly 1, primary, autosomal recessive Pathogenic:2
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Autosomal recessive primary microcephaly Pathogenic:1
Variant summary: MCPH1 c.2145G>A (p.Trp715X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 249568 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2145G>A in individuals affected with Primary Autosomal Recessive Microcephaly and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant pathogenic (n=4) and VUS (n=2) . Based on the evidence outlined above, the variant was classified as likely pathogenic. -
MCPH1-related disorder Uncertain:1
The MCPH1 c.2145G>A variant is predicted to result in premature protein termination (p.Trp715*). This variant was reported in an individual with transposition of the great arteries (Table 1, Blue et al 2022. PubMed ID: 34670123). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-6357381-G-A). Protein-truncating variants in this gene have been reported as causative for autosomal recessive primary microcephaly type one; however, there are no reported causative protein-truncating variants 3’ of the c.2145G>A variant (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Intellectual disability Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at