rs7965055

Variant names:

• chr12-7064316-C-G
• NM_001734.5:c.441C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-7064316-C-G
• chr12-7064316-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001734.5(C1S):​c.441C>G​(p.Cys147Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C147C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C1S NM_001734.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1S	NM_001734.5	c.441C>G	p.Cys147Trp	missense_variant	Exon 5 of 12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.441C>G	p.Cys147Trp	missense_variant	Exon 5 of 12		NP_958850.1
C1S	NM_001346850.2	c.-61C>G		5_prime_UTR_variant	Exon 4 of 11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.441C>G	p.Cys147Trp	missense_variant	Exon 5 of 12	1	NM_001734.5	ENSP00000354057.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D;D;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	.;.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-11	D;D;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.83
MutPred		0.95		Loss of stability (P = 0.1717);Loss of stability (P = 0.1717);Loss of stability (P = 0.1717);.;Loss of stability (P = 0.1717);
MVP		0.99
MPC		0.95
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7171620;