rs1284942525

chr2-127426097-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000312.4(PROC):c.548G>T(p.Cys183Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C183R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.61

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

LOC105373608 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 2-127426097-G-T is Pathogenic according to our data. Variant chr2-127426097-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536969.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.548G>T	p.Cys183Phe	missense_variant	7/9	ENST00000234071.8
LOC105373608	XR_007087228.1	n.3208C>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.548G>T	p.Cys183Phe	missense_variant	7/9	1	NM_000312.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251284 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 22, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 183 of the PROC protein (p.Cys183Phe). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PROC function (PMID: 22627591). 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 PROC protein function. ClinVar contains an entry for this variant (Variation ID: 536969). This variant is also known as Cys141Phe. This missense change has been observed in individuals with protein C deficiency (PMID: 22627591; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.0009%). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 01, 2022	The PROC c.548G>T (p.Cys183Phe) missense variant results in the substitution of cysteine at amino acid position 183 with phenylalanine. This variant has been reported in a heterozygous state in one individual with protein C deficiency with a measured protein C activity of 51% of normal (Caspers et al. 2012). The c.548G>T variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.548G>T (p.Cys183Phe) variant is classified as a variant of uncertain significance for protein C deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.8	D;D;D
REVEL	Pathogenic	0.83
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.69
MutPred		0.66		.;.;Loss of catalytic residue at P216 (P = 0.0145);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1284942525; hg19: chr2-128183673;