2-127419917-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000312.4(PROC):c.-21-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,952 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: PROC NM_000312.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009306
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.815

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-127419917-C-T is Benign according to our data. Variant chr2-127419917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 331101.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.-21-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000234071.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.-21-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000312.4	P1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00219 AC: 549 AN: 251080 Hom.: 0 AF XY: 0.00244 AC XY: 331 AN XY: 135798

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00286 AC: 4183 AN: 1461616 Hom.: 4 Cov.: 34 AF XY: 0.00285 AC XY: 2072 AN XY: 727136

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00180 AC XY: 134 AN XY: 74488

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00093
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: rs41269833; hg19: chr2-128177493;