chr2-127421438-G-T

Variant names:

• chr2-127421438-G-T
• rs121918149
• NM_000312.4:c.226G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_000312.4(PROC):​c.226G>T​(p.Val76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V76M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315
• Publications: 6 publications found

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]

PROC Gene-Disease associations (from GenCC):

• hereditary thrombophilia due to congenital protein C deficiency

  Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein C deficiency, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• thrombophilia due to protein C deficiency, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Vitamin K-dependent protein C light chain (size 154) in uniprot entity PROC_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-127421438-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.88339 (below the threshold of 3.09). Trascript score misZ: 1.6095 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein C deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21555328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.226G>T	p.Val76Leu	missense_variant	Exon 3 of 9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.226G>T	p.Val76Leu	missense_variant	Exon 3 of 9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D;D;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.17	T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.1	L;.;.;.;.
PhyloP100		0.32
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.62	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.30	.;T;T;T;.
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.015	B;.;.;.;B
Vest4		0.24
MutPred		0.53		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.81
MPC		0.45
ClinPred		0.028	T
GERP RS		1.9
Varity_R		0.57
gMVP		0.93
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs121918149; hg19: chr2-128179014;