2-127419885-G-A

Variant names:

• chr2-127419885-G-A
• rs371995306
• NM_000312.4:c.-21-37G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000312.4(PROC):​c.-21-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,613,528 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: PROC NM_000312.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.126
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-127419885-G-A is Benign according to our data. Variant chr2-127419885-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3892188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00265 (403/152344) while in subpopulation NFE AF = 0.00404 (275/68028). AF 95% confidence interval is 0.00365. There are 1 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.-21-37G>A		intron_variant	Intron 1 of 8	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.-21-37G>A		intron_variant	Intron 1 of 8	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00266 AC: 664 AN: 249966 AF XY: 0.00257

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00433

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00372 AC: 5438 AN: 1461184 Hom.: 19 Cov.: 34 AF XY: 0.00364 AC XY: 2648 AN XY: 726886

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.00130 AC: 58 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00364 AC: 193 AN: 53080

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5726

European-Non Finnish (NFE) AF: 0.00442 AC: 4918 AN: 1111800

Other (OTH) AF: 0.00348 AC: 210 AN: 60354

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74494

African (AFR) AF: 0.000746 AC: 31 AN: 41574

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00236

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive Benign:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.85
PhyloP100		0.13
PromoterAI		0.050	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs371995306; hg19: chr2-128177461;