rs12146727

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001734.5(C1S):c.356G>A(p.Arg119His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,484 control chromosomes in the GnomAD database, including 13,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.12 ( 1101 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12247 hom. )

Consequence

C1S
NM_001734.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001739502).

BP6

Variant 12-7063032-G-A is Benign according to our data. Variant chr12-7063032-G-A is described in ClinVar as [Benign]. Clinvar id is 1170123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7063032-G-A is described in Lovd as [Likely_benign]. Variant chr12-7063032-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1S	NM_001734.5 link	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 12	ENST00000360817.10	NP_001725.1	P09871
C1S	NM_201442.4 link	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 12		NP_958850.1	P09871
C1S	NM_001346850.2 link	c.-146G>A		5_prime_UTR_variant	Exon 3 of 11		NP_001333779.1	P09871F8WCZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10 link	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 12	1	NM_001734.5	ENSP00000354057.5		P09871

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18210

AN:

152024

Hom.:

1099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0858

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.0874

Gnomad SAS

AF:

0.0870

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.113

AC:

28439

AN:

251242

Hom.:

1800

AF XY:

0.114

AC XY:

15439

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0616

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0742

Gnomad SAS exome

AF:

0.0856

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.127

AC:

185439

AN:

1461342

Hom.:

12247

Cov.:

AF XY:

0.126

AC XY:

91587

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0994

Gnomad4 AMR exome

AF:

0.0647

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.0724

Gnomad4 SAS exome

AF:

0.0875

Gnomad4 FIN exome

AF:

0.177

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.126

GnomAD4 genome

AF:

0.120

AC:

18214

AN:

152142

Hom.:

1101

Cov.:

AF XY:

0.119

AC XY:

8855

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.0855

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.0865

Gnomad4 SAS

AF:

0.0871

Gnomad4 FIN

AF:

0.176

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.126

Hom.:

2309

Bravo

AF:

0.110

TwinsUK

AF:

0.137

AC:

509

ALSPAC

AF:

0.136

AC:

524

ESP6500AA

AF:

0.103

AC:

455

ESP6500EA

AF:

0.132

AC:

1135

ExAC

AF:

0.115

AC:

13989

Asia WGS

AF:

0.105

AC:

366

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.127

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;T;T;.;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

.;.;D;D;T

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M;.;.

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

D;D;D;.;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

D;D;D;.;T

Sift4G

Benign

0.13

T;T;T;T;D

Polyphen

0.95

P;P;P;.;.

Vest4

0.075

MPC

0.38

ClinPred

0.018

GERP RS

5.2

Varity_R

0.45

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over