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
Microcephaly 1, primary, autosomal recessive Pathogenic:2Uncertain:1
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This variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. -
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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. -
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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) -
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