Genetic Variant NM_001734.5:c.6-118C>T (chr12-7062357-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001734.5(C1S):c.6-118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 769,064 control chromosomes in the GnomAD database, including 6,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.13 ( 1280 hom., cov: 31)

Exomes 𝑓: 0.13 ( 5715 hom. )

Consequence

C1S
NM_001734.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.593

Publications

9 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-7062357-C-T is Benign according to our data. Variant chr12-7062357-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277281.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 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.6-118C>T	intron	N/A	NP_001725.1	P09871
C1S	NM_201442.4		c.6-118C>T	intron	N/A	NP_958850.1	P09871
C1S	NM_001346850.2		c.-289+440C>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.6-118C>T	intron	N/A	ENSP00000354057.5	P09871
C1S	ENST00000328916.7	TSL:1	c.6-118C>T	intron	N/A	ENSP00000328173.3	P09871
C1S	ENST00000402681.7	TSL:1	c.-289+440C>T	intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19637

AN:

151666

Hom.:

1274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0934

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0884

Gnomad SAS

AF:

0.0880

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.116

GnomAD4 exome

AF:

0.130

AC:

80549

AN:

617282

Hom.:

5715

Cov.:

AF XY:

0.129

AC XY:

42747

AN XY:

331756

show subpopulations

African (AFR)

AF:

0.110

AC:

1894

AN:

17224

American (AMR)

AF:

0.0762

AC:

2694

AN:

35370

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2331

AN:

20422

East Asian (EAS)

AF:

0.0720

AC:

2408

AN:

33426

South Asian (SAS)

AF:

0.0884

AC:

5706

AN:

64542

European-Finnish (FIN)

AF:

0.176

AC:

7657

AN:

43502

Middle Eastern (MID)

AF:

0.0950

AC:

241

AN:

2538

European-Non Finnish (NFE)

AF:

0.145

AC:

53398

AN:

367802

Other (OTH)

AF:

0.130

AC:

4220

AN:

32456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3122

6244

9367

12489

15611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.129

AC:

19649

AN:

151782

Hom.:

1280

Cov.:

AF XY:

0.128

AC XY:

9467

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.114

AC:

4714

AN:

41348

American (AMR)

AF:

0.0931

AC:

1420

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

367

AN:

3470

East Asian (EAS)

AF:

0.0875

AC:

453

AN:

5180

South Asian (SAS)

AF:

0.0879

AC:

422

AN:

4802

European-Finnish (FIN)

AF:

0.174

AC:

1825

AN:

10490

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.148

AC:

10085

AN:

67940

Other (OTH)

AF:

0.117

AC:

245

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

811

1622

2434

3245

4056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.137

Hom.:

1547

Bravo

AF:

0.121

Asia WGS

AF:

0.116

AC:

405

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.6

(source)

DANN

Benign

0.79

PhyloP100

-0.59

PromoterAI

0.0037

Neutral

(source)

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