rs35551093
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_024596.5(MCPH1):c.1719C>T(p.Ser573=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,218 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.013 ( 42 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 35 hom. )
Consequence
MCPH1
NM_024596.5 synonymous
NM_024596.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.267
Genes affected
MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 8-6445441-C-T is Benign according to our data. Variant chr8-6445441-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6445441-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.267 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1965/152334) while in subpopulation AFR AF= 0.0441 (1834/41566). AF 95% confidence interval is 0.0424. There are 42 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 42 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCPH1 | NM_024596.5 | c.1719C>T | p.Ser573= | synonymous_variant | 8/14 | ENST00000344683.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCPH1 | ENST00000344683.10 | c.1719C>T | p.Ser573= | synonymous_variant | 8/14 | 1 | NM_024596.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0128 AC: 1949AN: 152216Hom.: 39 Cov.: 33
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GnomAD3 exomes AF: 0.00313 AC: 781AN: 249332Hom.: 13 AF XY: 0.00248 AC XY: 335AN XY: 135348
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GnomAD4 exome AF: 0.00140 AC: 2049AN: 1461884Hom.: 35 Cov.: 45 AF XY: 0.00121 AC XY: 883AN XY: 727240
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GnomAD4 genome ? AF: 0.0129 AC: 1965AN: 152334Hom.: 42 Cov.: 33 AF XY: 0.0130 AC XY: 965AN XY: 74498
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 16, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2016 | 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. - |
Microcephaly 1, primary, autosomal recessive Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 01, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 14, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at