rs1143664

Variant names:

• chr12-7067743-A-G
• rs1143664
• NM_001734.5:c.1167A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001734.5(C1S):​c.1167A>G​(p.Pro389Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 1,613,332 control chromosomes in the GnomAD database, including 5,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (906 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4792 hom.)
• Consequence: C1S NM_001734.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.17
• Publications: 13 publications found

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]

C1S Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics
• complement component C1s deficiency

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 12-7067743-A-G is Benign according to our data. Variant chr12-7067743-A-G is described in ClinVar as Benign. ClinVar VariationId is 402440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001734.5. 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
	C1S	NM_001734.5	MANE Select	c.1167A>G	p.Pro389Pro	synonymous	Exon 10 of 12	NP_001725.1	P09871
	C1S	NM_201442.4		c.1167A>G	p.Pro389Pro	synonymous	Exon 10 of 12	NP_958850.1	P09871
	C1S	NM_001346850.2		c.666A>G	p.Pro222Pro	synonymous	Exon 9 of 11	NP_001333779.1	F8WCZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	ENST00000360817.10	TSL:1 MANE Select	c.1167A>G	p.Pro389Pro	synonymous	Exon 10 of 12	ENSP00000354057.5	P09871
	C1S	ENST00000328916.7	TSL:1	c.1167A>G	p.Pro389Pro	synonymous	Exon 10 of 12	ENSP00000328173.3	P09871
	C1S	ENST00000402681.7	TSL:1	c.666A>G	p.Pro222Pro	synonymous	Exon 9 of 11	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15130 AN: 152130 Hom.: 904 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0794 AC: 19953 AN: 251312 AF XY: 0.0800

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0557

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.0683

Gnomad NFE exome AF: 0.0785

Gnomad OTH exome AF: 0.0949

GnomAD4 exome AF: 0.0758 AC: 110782 AN: 1461084 Hom.: 4792 Cov.: 32 AF XY: 0.0765 AC XY: 55577 AN XY: 726892

African (AFR) AF: 0.171 AC: 5710 AN: 33448

American (AMR) AF: 0.0587 AC: 2625 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3675 AN: 26128

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39698

South Asian (SAS) AF: 0.0886 AC: 7636 AN: 86232

European-Finnish (FIN) AF: 0.0670 AC: 3581 AN: 53414

Middle Eastern (MID) AF: 0.166 AC: 956 AN: 5764

European-Non Finnish (NFE) AF: 0.0731 AC: 81281 AN: 1111306

Other (OTH) AF: 0.0873 AC: 5271 AN: 60370

GnomAD4 genome AF: 0.0995 AC: 15150 AN: 152248 Hom.: 906 Cov.: 32 AF XY: 0.0982 AC XY: 7307 AN XY: 74442

African (AFR) AF: 0.166 AC: 6876 AN: 41540

American (AMR) AF: 0.0841 AC: 1286 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5190

South Asian (SAS) AF: 0.0902 AC: 435 AN: 4822

European-Finnish (FIN) AF: 0.0615 AC: 653 AN: 10616

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0738 AC: 5021 AN: 68010

Other (OTH) AF: 0.112 AC: 236 AN: 2108

Alfa AF: 0.0852 Hom.: 1316

Bravo AF: 0.104

Asia WGS AF: 0.0720 AC: 248 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.17
DANN	Benign	0.28
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1143664; hg19: chr12-7175047; COSMIC: COSV61072528; COSMIC: COSV61072528;