rs201128010
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_024596.5(MCPH1):c.1186C>A(p.His396Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H396Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_024596.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCPH1 | NM_024596.5 | c.1186C>A | p.His396Asn | missense_variant | 8/14 | ENST00000344683.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCPH1 | ENST00000344683.10 | c.1186C>A | p.His396Asn | missense_variant | 8/14 | 1 | NM_024596.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000180 AC: 45AN: 249326Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135360
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461840Hom.: 0 Cov.: 51 AF XY: 0.0000303 AC XY: 22AN XY: 727224
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74356
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 22, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2023 | The c.1186C>A (p.H396N) alteration is located in exon 8 (coding exon 8) of the MCPH1 gene. This alteration results from a C to A substitution at nucleotide position 1186, causing the histidine (H) at amino acid position 396 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Microcephaly 1, primary, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
MCPH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The MCPH1 c.1186C>A variant is predicted to result in the amino acid substitution p.His396Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 396 of the MCPH1 protein (p.His396Asn). This variant is present in population databases (rs201128010, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 211444). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at