chr2-127428530-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PM5PP5_ModerateBP4
The NM_000312.4(PROC):c.970G>A(p.Gly324Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G324R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000312.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PROC | ENST00000234071.8 | c.970G>A | p.Gly324Ser | missense_variant | 9/9 | 1 | NM_000312.4 | ENSP00000234071.4 | ||
PROC | ENST00000409048.1 | c.1072G>A | p.Gly358Ser | missense_variant | 7/7 | 5 | ENSP00000386679.1 | |||
PROC | ENST00000402125.2 | c.292G>A | p.Gly98Ser | missense_variant | 2/2 | 2 | ENSP00000384225.2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251216Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135834
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461582Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727098
GnomAD4 genome AF: 0.0000459 AC: 7AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74508
ClinVar
Submissions by phenotype
Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 10, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the PROC protein (p.Gly324Ser). This variant is present in population databases (rs571278160, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of protein C deficiency (PMID: 7831652, 27517348; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as G282S. ClinVar contains an entry for this variant (Variation ID: 568761). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PROC protein function with a negative predictive value of 80%. This variant disrupts the p.Gly324 amino acid residue in PROC. Other variant(s) that disrupt this residue have been observed in individuals with PROC-related conditions (PMID: 7792728), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at