rs12146727

Positions:

• chr12-7063032-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1101 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12247 hom.)
• Consequence: C1S NM_001734.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.18

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
C1S	NM_001734.5	c.356G>A	p.Arg119His	missense_variant	4/12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.356G>A	p.Arg119His	missense_variant	4/12		NP_958850.1
C1S	NM_001346850.2	c.-146G>A		5_prime_UTR_variant	3/11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.356G>A	p.Arg119His	missense_variant	4/12	1	NM_001734.5	ENSP00000354057.5

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18210 AN: 152024 Hom.: 1099 Cov.: 32

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

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.: 34 AF XY: 0.126 AC XY: 91587 AN XY: 726982

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.: 32 AF XY: 0.119 AC XY: 8855 AN XY: 74376

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

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
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	D
LIST_S2	Uncertain	0.89	.;.;D;D;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M;.;.
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs12146727; hg19: chr12-7170336; COSMIC: COSV61070479; COSMIC: COSV61070479;