Genetic Variant C1S:c.5+141C>T (chr12-7062058-C-T) – ACMG Classification: Benign (-20 pts)

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.5+141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 835,256 control chromosomes in the GnomAD database, including 4,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2580 hom., cov: 30)

Exomes 𝑓: 0.054 ( 2032 hom. )

Consequence

C1S
NM_001734.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.985

Publications

1 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 (BayesDel_noAF=-0.97).

BP6

Variant 12-7062058-C-T is Benign according to our data. Variant chr12-7062058-C-T is described in ClinVar as Benign. ClinVar VariationId is 1273754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 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	Effect	Exon Rank	Protein	UniProt
C1S	NM_001734.5	MANE Select	c.5+141C>T	intron	N/A	NP_001725.1	P09871
C1S	NM_201442.4		c.5+141C>T	intron	N/A	NP_958850.1	P09871
C1S	NM_001346850.2		c.-289+141C>T	intron	N/A	NP_001333779.1	F8WCZ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C1S	ENST00000360817.10	TSL:1 MANE Select	c.5+141C>T	intron	N/A	ENSP00000354057.5	P09871
C1S	ENST00000328916.7	TSL:1	c.5+141C>T	intron	N/A	ENSP00000328173.3	P09871
C1S	ENST00000402681.7	TSL:1	c.-289+141C>T	intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19272

AN:

151110

Hom.:

2561

Cov.:

show subpopulations

Gnomad AFR

AF:

0.335

Gnomad AMI

AF:

0.0604

Gnomad AMR

AF:

0.0771

Gnomad ASJ

AF:

0.0752

Gnomad EAS

AF:

0.0575

Gnomad SAS

AF:

0.0841

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0427

Gnomad OTH

AF:

0.126

GnomAD4 exome

AF:

0.0542

AC:

37108

AN:

684028

Hom.:

2032

Cov.:

AF XY:

0.0548

AC XY:

19971

AN XY:

364606

show subpopulations

African (AFR)

AF:

0.330

AC:

5886

AN:

17832

American (AMR)

AF:

0.0485

AC:

1763

AN:

36388

Ashkenazi Jewish (ASJ)

AF:

0.0819

AC:

1685

AN:

20562

East Asian (EAS)

AF:

0.0303

AC:

993

AN:

32806

South Asian (SAS)

AF:

0.0778

AC:

5205

AN:

66870

European-Finnish (FIN)

AF:

0.0226

AC:

829

AN:

36602

Middle Eastern (MID)

AF:

0.175

AC:

719

AN:

4102

European-Non Finnish (NFE)

AF:

0.0400

AC:

17349

AN:

434152

Other (OTH)

AF:

0.0772

AC:

2679

AN:

34714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1662

3323

4985

6646

8308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.128

AC:

19343

AN:

151228

Hom.:

2580

Cov.:

AF XY:

0.126

AC XY:

9287

AN XY:

73894

show subpopulations

African (AFR)

AF:

0.336

AC:

13739

AN:

40906

American (AMR)

AF:

0.0770

AC:

1171

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.0752

AC:

261

AN:

3470

East Asian (EAS)

AF:

0.0576

AC:

297

AN:

5154

South Asian (SAS)

AF:

0.0841

AC:

401

AN:

4766

European-Finnish (FIN)

AF:

0.0184

AC:

194

AN:

10526

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0427

AC:

2902

AN:

67900

Other (OTH)

AF:

0.128

AC:

269

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

660

1320

1979

2639

3299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0938

Hom.:

185

Bravo

AF:

0.141

Asia WGS

AF:

0.104

AC:

360

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

1.4

(source)

DANN

Benign

0.56

PhyloP100

-0.98

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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