Genetic Variant C1S:c.5+203_5+204dupAA (chr12-7062107-T-TAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001734.5(C1S):c.5+203_5+204dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 528,318 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0062 ( 13 hom., cov: 27)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

C1S
NM_001734.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.347

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00617 (876/141996) while in subpopulation AFR AF = 0.0176 (678/38502). AF 95% confidence interval is 0.0165. There are 13 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

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+203_5+204dupAA	intron	N/A	NP_001725.1	P09871
C1S	NM_201442.4		c.5+203_5+204dupAA	intron	N/A	NP_958850.1	P09871
C1S	NM_001346850.2		c.-289+203_-289+204dupAA	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+203_5+204dupAA	intron	N/A	ENSP00000354057.5	P09871
C1S	ENST00000328916.7	TSL:1	c.5+203_5+204dupAA	intron	N/A	ENSP00000328173.3	P09871
C1S	ENST00000402681.7	TSL:1	c.-289+203_-289+204dupAA	intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

872

AN:

141932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00840

Gnomad ASJ

AF:

0.000300

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.000223

Gnomad FIN

AF:

0.000114

Gnomad MID

AF:

0.0236

Gnomad NFE

AF:

0.000726

Gnomad OTH

AF:

0.0104

GnomAD4 exome

AF:

0.00235

AC:

906

AN:

386322

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

432

AN XY:

207926

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0218

AC:

228

AN:

10478

American (AMR)

AF:

0.00575

AC:

AN:

17038

Ashkenazi Jewish (ASJ)

AF:

0.00210

AC:

AN:

11924

East Asian (EAS)

AF:

0.000732

AC:

AN:

24586

South Asian (SAS)

AF:

0.000534

AC:

AN:

43072

European-Finnish (FIN)

AF:

0.000528

AC:

AN:

22744

Middle Eastern (MID)

AF:

0.00924

AC:

AN:

1732

European-Non Finnish (NFE)

AF:

0.00161

AC:

376

AN:

233060

Other (OTH)

AF:

0.00507

AC:

110

AN:

21688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00617

AC:

876

AN:

141996

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

395

AN XY:

68860

show subpopulations

African (AFR)

AF:

0.0176

AC:

678

AN:

38502

American (AMR)

AF:

0.00839

AC:

119

AN:

14178

Ashkenazi Jewish (ASJ)

AF:

0.000300

AC:

AN:

3330

East Asian (EAS)

AF:

0.000203

AC:

AN:

4916

South Asian (SAS)

AF:

0.000223

AC:

AN:

4476

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

8790

Middle Eastern (MID)

AF:

0.0257

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000726

AC:

AN:

64714

Other (OTH)

AF:

0.0109

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-7062107-TAAAAA-TAAAAAAA

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