rs144851896

chr12-7069868-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001734.5(C1S):c.1284C>G(p.Pro428=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000681 in 1,614,044 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P428P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (16 hom.)
• Consequence: C1S NM_001734.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.215

Genes affected

C1S (HGNC:1247): (complement C1s) This gene encodes a serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-7069868-C-G is Benign according to our data. Variant chr12-7069868-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 402441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7069868-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000679 (993/1461736) while in subpopulation MID AF= 0.0381 (220/5768). AF 95% confidence interval is 0.034. There are 16 homozygotes in gnomad4_exome. There are 506 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1S	NM_001734.5	c.1284C>G	p.Pro428=	synonymous_variant	12/12	ENST00000360817.10
C1S	NM_201442.4	c.1284C>G	p.Pro428=	synonymous_variant	12/12
C1S	NM_001346850.2	c.783C>G	p.Pro261=	synonymous_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1S	ENST00000360817.10	c.1284C>G	p.Pro428=	synonymous_variant	12/12	1	NM_001734.5	P1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000852 AC: 214 AN: 251106 Hom.: 0 AF XY: 0.000884 AC XY: 120 AN XY: 135796

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000776

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000679 AC: 993 AN: 1461736 Hom.: 16 Cov.: 32 AF XY: 0.000696 AC XY: 506 AN XY: 727198

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74458

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000975

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	C1S: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.5
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144851896; hg19: chr12-7177172; COSMIC: COSV61070263; COSMIC: COSV61070263;