2-127419801-C-T

Position:

• chr2-127419801-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000312.4(PROC):​c.-21-121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,552,480 control chromosomes in the GnomAD database, including 260,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22501 hom., cov: 33)
  • Exomes 𝑓: 0.58 (238240 hom.)
• Consequence: PROC NM_000312.4 intron
• Scores: Splicing: ADA: 0.00007462
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.301

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 2-127419801-C-T is Benign according to our data. Variant chr2-127419801-C-T is described in ClinVar as [Benign]. Clinvar id is 1220858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.-21-121C>T		intron_variant		ENST00000234071.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.-21-121C>T		intron_variant		1	NM_000312.4	P1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79427 AN: 151976 Hom.: 22479 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.532

GnomAD4 exome AF: 0.578 AC: 809900 AN: 1400386 Hom.: 238240 Cov.: 39 AF XY: 0.578 AC XY: 399434 AN XY: 691152

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.740

Gnomad4 ASJ exome AF: 0.505

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.648

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.523 AC: 79486 AN: 152094 Hom.: 22501 Cov.: 33 AF XY: 0.532 AC XY: 39594 AN XY: 74364

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.825

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.536

Alfa AF: 0.574 Hom.: 46652

Bravo AF: 0.515

Asia WGS AF: 0.721 AC: 2504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	16
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1158867; hg19: chr2-128177377;