2-127419801-C-T

Variant names:

• chr2-127419801-C-T
• rs1158867
• NM_000312.4:c.-21-121C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001375602.1(PROC):​c.47-5C>T variant causes a splice region, 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_001375602.1 splice_region, intron
• Scores: Splicing: ADA: 0.00007462
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.301
• Publications: 38 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):

• thrombophilia due to protein C deficiency, autosomal dominant

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

  Inheritance: SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375602.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	NM_000312.4	MANE Select	c.-21-121C>T		intron	N/A	NP_000303.1	P04070-1
	PROC	NM_001375613.1		c.-142C>T		5_prime_UTR	Exon 1 of 8	NP_001362542.1	P04070-1
	PROC	NM_001375607.1		c.47-69C>T		intron	N/A	NP_001362536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.-21-121C>T		intron	N/A	ENSP00000234071.4	P04070-1
	PROC	ENST00000883897.1		c.-142C>T		5_prime_UTR	Exon 1 of 7	ENSP00000553956.1
	PROC	ENST00000883902.1		c.-142C>T		5_prime_UTR	Exon 1 of 7	ENSP00000553961.1

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

African (AFR) AF: 0.293 AC: 9322 AN: 31824

American (AMR) AF: 0.740 AC: 27419 AN: 37030

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 12440 AN: 24642

East Asian (EAS) AF: 0.862 AC: 31113 AN: 36110

South Asian (SAS) AF: 0.567 AC: 45536 AN: 80308

European-Finnish (FIN) AF: 0.648 AC: 31061 AN: 47940

Middle Eastern (MID) AF: 0.486 AC: 2478 AN: 5102

European-Non Finnish (NFE) AF: 0.572 AC: 617217 AN: 1079460

Other (OTH) AF: 0.575 AC: 33314 AN: 57970

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

African (AFR) AF: 0.307 AC: 12715 AN: 41480

American (AMR) AF: 0.658 AC: 10054 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3468

East Asian (EAS) AF: 0.825 AC: 4265 AN: 5172

South Asian (SAS) AF: 0.582 AC: 2806 AN: 4822

European-Finnish (FIN) AF: 0.660 AC: 6991 AN: 10590

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.576 AC: 39170 AN: 67964

Other (OTH) AF: 0.536 AC: 1133 AN: 2112

Alfa AF: 0.562 Hom.: 97398

Bravo AF: 0.515

Asia WGS AF: 0.721 AC: 2504 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	16
DANN	Benign	0.70
PhyloP100		0.30
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1158867; hg19: chr2-128177377;