2-127419994-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_000312.4(PROC):c.52G>A(p.Gly18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,608 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000312.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251292Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135850
GnomAD4 exome AF: 0.000122 AC: 178AN: 1461346Hom.: 2 Cov.: 34 AF XY: 0.000125 AC XY: 91AN XY: 726986
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74460
ClinVar
Submissions by phenotype
Thrombophilia due to protein C deficiency, autosomal dominant Uncertain:2
This sequence change replaces glycine with serine at codon 18 of the PROC protein (p.Gly18Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs146793243, ExAC 0.03%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 22627591). This variant is also known as Gly25Ser. ClinVar contains an entry for this variant (Variation ID: 161337). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at