2-127428495-C-T

Position:

• chr2-127428495-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000312.4(PROC):​c.935C>T​(p.Ser312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,762 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S312S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.69

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Peptidase S1 (size 238) in uniprot entity PROC_HUMAN there are 59 pathogenic changes around while only 10 benign (86%) in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 2-127428495-C-T is Pathogenic according to our data. Variant chr2-127428495-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 680.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.935C>T	p.Ser312Leu	missense_variant	9/9	ENST00000234071.8
LOC105373608	XR_007087228.1	n.1041-231G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.935C>T	p.Ser312Leu	missense_variant	9/9	1	NM_000312.4	P1
PROC	ENST00000409048.1	c.1037C>T	p.Ser346Leu	missense_variant	7/7	5
PROC	ENST00000402125.2	c.260C>T	p.Ser87Leu	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251348 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PROC function (PMID: 11380450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 680). This variant is also known as 8524C>T, p.Ser270Leu. This missense change has been observed in individuals with deep vein thrombosis, pulmonary embolism, and protein C deficiency (PMID: 7482420, 11380450, 22545135). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918160, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 312 of the PROC protein (p.Ser312Leu). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.17	A;A;A;A
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.60
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.82		.;Loss of sheet (P = 0.0817);
MVP		0.95
MPC		1.2
ClinPred		0.82	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918160; hg19: chr2-128186071;