NM_001734.5:c.356G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.18

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, periodontal type 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics
complement component C1s deficiency
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Ehlers-Danlos syndrome, periodontitis type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

C1S links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001734.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1S	NM_001734.5	MANE Select	c.356G>A	p.Arg119His	missense	Exon 4 of 12	NP_001725.1	P09871
C1S	NM_201442.4		c.356G>A	p.Arg119His	missense	Exon 4 of 12	NP_958850.1	P09871
C1S	NM_001346850.2		c.-146G>A		5_prime_UTR	Exon 3 of 11	NP_001333779.1	F8WCZ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1S	ENST00000360817.10	TSL:1 MANE Select	c.356G>A	p.Arg119His	missense	Exon 4 of 12	ENSP00000354057.5	P09871
C1S	ENST00000328916.7	TSL:1	c.356G>A	p.Arg119His	missense	Exon 4 of 12	ENSP00000328173.3	P09871
C1S	ENST00000402681.7	TSL:1	c.-146G>A		5_prime_UTR	Exon 3 of 11	ENSP00000384171.3	F8WCZ6

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

GnomAD2 exomes

AF:

0.113

AC:

28439

AN:

251242

AF XY:

0.114

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

8354

16709

25063

33418

41772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5242

10484

15726

20968

26210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.120

AC:

18214

AN:

152142

Hom.:

1101

Cov.:

AF XY:

0.119

AC XY:

8855

AN XY:

74376

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.137

AC:

9326

AN:

67994

Other (OTH)

AF:

0.103

AC:

219

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

818

1636

2454

3272

4090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

2.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.16

Sift

Uncertain

0.0010

Sift4G

Benign

0.13

Polyphen

0.95

Vest4

0.075

MPC

0.38

ClinPred

0.018

GERP RS

5.2

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.45

gMVP

0.52

Mutation Taster

=284/16

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over