rs121918144

Positions:

• chr2-127428462-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000234071.8(PROC):​c.902C>T​(p.Ala301Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,824 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A301T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PROC ENST00000234071.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.97

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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000234071.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-127428461-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-127428462-C-T is Pathogenic according to our data. Variant chr2-127428462-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 660.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROC	NM_000312.4	c.902C>T	p.Ala301Val	missense_variant	9/9	ENST00000234071.8	NP_000303.1
LOC105373608	XR_007087228.1	n.1041-198G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.902C>T	p.Ala301Val	missense_variant	9/9	1	NM_000312.4	ENSP00000234071	P1
PROC	ENST00000409048.1	c.1004C>T	p.Ala335Val	missense_variant	7/7	5		ENSP00000386679
PROC	ENST00000402125.2	c.227C>T	p.Ala76Val	missense_variant	2/2	2		ENSP00000384225

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

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.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2024

Not observed at significant frequency in large population cohorts (PMID: 27535533); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1678832, 27535533) -

Thrombophilia due to protein C deficiency, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.95		.;Loss of disorder (P = 0.0942);
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.99

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: rs121918144; hg19: chr2-128186038;