rs121909582

Variant names:

• chr12-7070184-C-G
• rs121909582
• NM_001734.5:c.1600C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-7070184-C-G
• chr12-7070184-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001734.5(C1S):​c.1600C>G​(p.Arg534Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R534Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1S NM_001734.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 0 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), G2P, Ambry Genetics, Genomics England PanelApp
• complement component C1s deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1S	NM_001734.5	c.1600C>G	p.Arg534Gly	missense_variant	Exon 12 of 12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.1600C>G	p.Arg534Gly	missense_variant	Exon 12 of 12		NP_958850.1
C1S	NM_001346850.2	c.1099C>G	p.Arg367Gly	missense_variant	Exon 11 of 11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.1600C>G	p.Arg534Gly	missense_variant	Exon 12 of 12	1	NM_001734.5	ENSP00000354057.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;D;.;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;.;T;T;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.
PhyloP100		3.0
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.8	D;D;D;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D;D;D;.;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.70	P;P;P;.;.
Vest4		0.35
MutPred		0.78		Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);.;.;
MVP		0.91
MPC		0.54
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.86
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs121909582; hg19: chr12-7177488;