chr12-122473630-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_017612.5(ZCCHC8):c.1991G>A(p.Ser664Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_017612.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZCCHC8 | ENST00000633063.3 | c.1991G>A | p.Ser664Asn | missense_variant | Exon 14 of 14 | 1 | NM_017612.5 | ENSP00000488055.1 | ||
ZCCHC8 | ENST00000536306.5 | c.1277G>A | p.Ser426Asn | missense_variant | Exon 12 of 12 | 1 | ENSP00000441423.1 | |||
ZCCHC8 | ENST00000543897.5 | c.1277G>A | p.Ser426Asn | missense_variant | Exon 12 of 12 | 1 | ENSP00000438993.1 | |||
ZCCHC8 | ENST00000538116.5 | n.1092G>A | non_coding_transcript_exon_variant | Exon 3 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249266Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135222
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727138
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 664 of the ZCCHC8 protein (p.Ser664Asn). This variant is present in population databases (rs770606298, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ZCCHC8-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ZCCHC8 protein function with a positive predictive value of 80%. 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