chr2-127423407-A-C

Variant names:

• chr2-127423407-A-C
• rs368367611
• NM_000312.4:c.534A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000312.4(PROC):​c.534A>C​(p.Ala178Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A178A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PROC NM_000312.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.07595
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• 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]

MIR4783 (HGNC:41874): (microRNA 4783) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000312.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	NM_000312.4	MANE Select	c.534A>C	p.Ala178Ala	splice_region synonymous	Exon 6 of 9	NP_000303.1
	PROC	NM_001375607.1		c.720A>C	p.Ala240Ala	splice_region synonymous	Exon 5 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.717A>C	p.Ala239Ala	splice_region synonymous	Exon 6 of 9	NP_001362531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.534A>C	p.Ala178Ala	splice_region synonymous	Exon 6 of 9	ENSP00000234071.4
	PROC	ENST00000409048.1	TSL:5	c.636A>C	p.Ala212Ala	splice_region synonymous	Exon 4 of 7	ENSP00000386679.1
	PROC	ENST00000402125.2	TSL:2	c.117A>C	p.Ala39Ala	splice_region synonymous	Exon 1 of 2	ENSP00000384225.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397354 Hom.: 0 Cov.: 75 AF XY: 0.00 AC XY: 0 AN XY: 689284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31450

American (AMR) AF: 0.00 AC: 0 AN: 35740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35688

South Asian (SAS) AF: 0.00 AC: 0 AN: 79068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078872

Other (OTH) AF: 0.0000172 AC: 1 AN: 57980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.56
PhyloP100		-0.44
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.076
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.080		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: rs368367611; hg19: chr2-128180983;