12-7062107-TAAAAA-TAAAAAA

Variant names:

• chr12-7062107-T-TA
• rs376183132
• NM_001734.5:c.5+204dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001734.5(C1S):​c.5+204dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 516,112 control chromosomes in the GnomAD database, including 2,018 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (2001 hom., cov: 27)
  • Exomes 𝑓: 0.092 (17 hom.)
• Consequence: C1S NM_001734.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.347
• Publications: 0 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), 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-7062107-T-TA is Benign according to our data. Variant chr12-7062107-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1282313.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	NM_001734.5	MANE Select	c.5+204dupA		intron	N/A	NP_001725.1	P09871
	C1S	NM_201442.4		c.5+204dupA		intron	N/A	NP_958850.1	P09871
	C1S	NM_001346850.2		c.-289+204dupA		intron	N/A	NP_001333779.1	F8WCZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	ENST00000360817.10	TSL:1 MANE Select	c.5+204dupA		intron	N/A	ENSP00000354057.5	P09871
	C1S	ENST00000328916.7	TSL:1	c.5+204dupA		intron	N/A	ENSP00000328173.3	P09871
	C1S	ENST00000402681.7	TSL:1	c.-289+204dupA		intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes AF: 0.123 AC: 17420 AN: 141768 Hom.: 1997 Cov.: 27

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.0590

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0820

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.0864

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.0920 AC: 34421 AN: 374280 Hom.: 17 Cov.: 0 AF XY: 0.0915 AC XY: 18424 AN XY: 201254

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

African (AFR) AF: 0.276 AC: 2848 AN: 10326

American (AMR) AF: 0.0731 AC: 1208 AN: 16534

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 1404 AN: 11588

East Asian (EAS) AF: 0.0750 AC: 1801 AN: 24028

South Asian (SAS) AF: 0.101 AC: 4156 AN: 41126

European-Finnish (FIN) AF: 0.0698 AC: 1545 AN: 22148

Middle Eastern (MID) AF: 0.145 AC: 246 AN: 1700

European-Non Finnish (NFE) AF: 0.0838 AC: 18910 AN: 225780

Other (OTH) AF: 0.109 AC: 2303 AN: 21050

⚠️ 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.

GnomAD4 genome AF: 0.123 AC: 17461 AN: 141832 Hom.: 2001 Cov.: 27 AF XY: 0.121 AC XY: 8340 AN XY: 68776

African (AFR) AF: 0.309 AC: 11868 AN: 38444

American (AMR) AF: 0.0710 AC: 1005 AN: 14160

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 273 AN: 3330

East Asian (EAS) AF: 0.0615 AC: 302 AN: 4912

South Asian (SAS) AF: 0.0865 AC: 387 AN: 4476

European-Finnish (FIN) AF: 0.0272 AC: 238 AN: 8760

Middle Eastern (MID) AF: 0.163 AC: 44 AN: 270

European-Non Finnish (NFE) AF: 0.0474 AC: 3063 AN: 64666

Other (OTH) AF: 0.119 AC: 229 AN: 1932

Alfa AF: 0.0136 Hom.: 3

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs376183132; hg19: chr12-7169411;