rs5937

chr2-127427194-T-Achr2-127427194-T-Cchr2-127427194-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000312.4(PROC):c.768T>A(p.Asp256Glu) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D256D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57

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 Uncertain_significance. Variant got 2 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, 2 uncertain in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07397172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.768T>A	p.Asp256Glu	missense_variant	8/9	ENST00000234071.8
LOC105373608	XR_007087228.1	n.2111A>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.768T>A	p.Asp256Glu	missense_variant	8/9	1	NM_000312.4	P1
PROC	ENST00000409048.1	c.870T>A	p.Asp290Glu	missense_variant	6/7	5
PROC	ENST00000402125.2	c.121-1163T>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.069
Dann	Benign	0.81
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.083	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.080	N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.69	N;N
REVEL	Benign	0.25
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.085
MutPred		0.34		.;Gain of sheet (P = 0.0827);
MVP		0.61
MPC		0.41
ClinPred		0.039	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.79

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: rs5937; hg19: chr2-128184770;