chr2-127421438-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000312.4(PROC):c.226G>A(p.Val76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000312.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250918Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135748
GnomAD4 exome AF: 0.000140 AC: 205AN: 1461556Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 87AN XY: 727048
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74382
ClinVar
Submissions by phenotype
Abnormal thrombosis Pathogenic:1
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Thrombophilia due to protein C deficiency, autosomal recessive Pathogenic:1
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Cerebral palsy Pathogenic:1
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PROC-related disorder Pathogenic:1
The PROC c.226G>A variant is predicted to result in the amino acid substitution p.Val76Met. This variant is also described with legacy nomenclature as p.Val34Met, and was reported along with a second potentially causative variant in three individuals from a single family with protein C deficiency (Long. 1992. PubMed ID: 1347706). This variant has also been reported in the heterozygous state in two patients with an unspecified bleeding, thrombotic, or platelet disorder (Wu. 2013. PubMed ID: 24051141; Table S3, Downes. 2019. PubMed ID: 31064749). In vitro functional studies found this variant results in decreased protein synthesis and reduced activation (Wu. 2013. PubMed ID: 24051141).This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at