rs121434305
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024596.5(MCPH1):c.74C>G(p.Ser25Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000753 in 1,461,784 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely benign.
Frequency
Consequence
NM_024596.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCPH1 | NM_024596.5 | c.74C>G | p.Ser25Ter | stop_gained | 2/14 | ENST00000344683.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCPH1 | ENST00000344683.10 | c.74C>G | p.Ser25Ter | stop_gained | 2/14 | 1 | NM_024596.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249568Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135406
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727202
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly 1, primary, autosomal recessive Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2006 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3454). This premature translational stop signal has been observed in individual(s) with clinical features of MCPH1-related conditions (PMID: 12046007). This variant is present in population databases (rs121434305, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ser25*) in the MCPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCPH1 are known to be pathogenic (PMID: 20978018). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at