12-7062107-TAAAAA-TAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001734.5(C1S):​c.5+204delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 459,676 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 27)
  • Exomes 𝑓: 0.28 (2 hom.)
• Consequence: C1S NM_001734.5 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	NM_001734.5	MANE Select	c.5+204delA		intron	N/A	NP_001725.1	P09871
	C1S	NM_201442.4		c.5+204delA		intron	N/A	NP_958850.1	P09871
	C1S	NM_001346850.2		c.-289+204delA		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+204delA		intron	N/A	ENSP00000354057.5	P09871
	C1S	ENST00000328916.7	TSL:1	c.5+204delA		intron	N/A	ENSP00000328173.3	P09871
	C1S	ENST00000402681.7	TSL:1	c.-289+204delA		intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 304 AN: 141428 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00205

Gnomad ASJ AF: 0.00211

Gnomad EAS AF: 0.00305

Gnomad SAS AF: 0.000670

Gnomad FIN AF: 0.00966

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00261

GnomAD4 exome AF: 0.279 AC: 88886 AN: 318186 Hom.: 2 Cov.: 0 AF XY: 0.280 AC XY: 47797 AN XY: 170942

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

African (AFR) AF: 0.138 AC: 1314 AN: 9542

American (AMR) AF: 0.308 AC: 3990 AN: 12950

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 2574 AN: 10312

East Asian (EAS) AF: 0.292 AC: 6085 AN: 20836

South Asian (SAS) AF: 0.297 AC: 9525 AN: 32020

European-Finnish (FIN) AF: 0.270 AC: 5244 AN: 19398

Middle Eastern (MID) AF: 0.224 AC: 347 AN: 1552

European-Non Finnish (NFE) AF: 0.285 AC: 54990 AN: 193208

Other (OTH) AF: 0.262 AC: 4817 AN: 18368

⚠️ 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: 0.00216 AC: 306 AN: 141490 Hom.: 0 Cov.: 27 AF XY: 0.00271 AC XY: 186 AN XY: 68590

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

African (AFR) AF: 0.000728 AC: 28 AN: 38478

American (AMR) AF: 0.00205 AC: 29 AN: 14124

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 7 AN: 3324

East Asian (EAS) AF: 0.00306 AC: 15 AN: 4908

South Asian (SAS) AF: 0.000671 AC: 3 AN: 4470

European-Finnish (FIN) AF: 0.00966 AC: 83 AN: 8588

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00209 AC: 135 AN: 64512

Other (OTH) AF: 0.00259 AC: 5 AN: 1930

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV61071215; COSMIC: COSV61071215;