rs12146727

Variant names:

• chr12-7063032-G-A
• rs12146727
• NM_001734.5:c.356G>A

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R119C) has been classified as Uncertain significance.

• 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
• Publications: 38 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: Benign. The variant received -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 VariationId is 1170123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 12		NP_958850.1
C1S	NM_001346850.2	c.-146G>A		5_prime_UTR_variant	Exon 3 of 11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.356G>A	p.Arg119His	missense_variant	Exon 4 of 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

GnomAD2 exomes AF: 0.113 AC: 28439 AN: 251242 AF XY: 0.114

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 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

African (AFR) AF: 0.0994 AC: 3328 AN: 33476

American (AMR) AF: 0.0647 AC: 2895 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2831 AN: 26134

East Asian (EAS) AF: 0.0724 AC: 2875 AN: 39698

South Asian (SAS) AF: 0.0875 AC: 7544 AN: 86252

European-Finnish (FIN) AF: 0.177 AC: 9423 AN: 53234

Middle Eastern (MID) AF: 0.0902 AC: 520 AN: 5766

European-Non Finnish (NFE) AF: 0.133 AC: 148400 AN: 1111672

Other (OTH) AF: 0.126 AC: 7623 AN: 60386

GnomAD4 genome AF: 0.120 AC: 18214 AN: 152142 Hom.: 1101 Cov.: 32 AF XY: 0.119 AC XY: 8855 AN XY: 74376

African (AFR) AF: 0.101 AC: 4172 AN: 41504

American (AMR) AF: 0.0855 AC: 1308 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3468

East Asian (EAS) AF: 0.0865 AC: 448 AN: 5180

South Asian (SAS) AF: 0.0871 AC: 420 AN: 4822

European-Finnish (FIN) AF: 0.176 AC: 1855 AN: 10560

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9326 AN: 67994

Other (OTH) AF: 0.103 AC: 219 AN: 2116

Alfa AF: 0.126 Hom.: 4729

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

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	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;.;.
PhyloP100		2.2
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
PromoterAI		-0.025	Neutral
Varity_R		0.45
gMVP		0.52
Mutation Taster		=284/16	polymorphism (auto)

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

Other links and lift over

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