12-7062107-TAAAAA-TAAAAAAAA

Variant names:

• chr12-7062107-T-TAAA
• rs376183132
• NM_001734.5:c.5+202_5+204dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001734.5(C1S):​c.5+202_5+204dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 387,404 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000023 (0 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: Uncertain_significance. The variant received 0 ACMG points.

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+202_5+204dupAAA		intron	N/A	NP_001725.1	P09871
	C1S	NM_201442.4		c.5+202_5+204dupAAA		intron	N/A	NP_958850.1	P09871
	C1S	NM_001346850.2		c.-289+202_-289+204dupAAA		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+202_5+204dupAAA		intron	N/A	ENSP00000354057.5	P09871
	C1S	ENST00000328916.7	TSL:1	c.5+202_5+204dupAAA		intron	N/A	ENSP00000328173.3	P09871
	C1S	ENST00000402681.7	TSL:1	c.-289+202_-289+204dupAAA		intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.0000232 AC: 9 AN: 387404 Hom.: 0 Cov.: 0 AF XY: 0.0000288 AC XY: 6 AN XY: 208490

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

African (AFR) AF: 0.000284 AC: 3 AN: 10548

American (AMR) AF: 0.0000585 AC: 1 AN: 17094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11956

East Asian (EAS) AF: 0.00 AC: 0 AN: 24674

South Asian (SAS) AF: 0.00 AC: 0 AN: 43124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1736

European-Non Finnish (NFE) AF: 0.0000128 AC: 3 AN: 233712

Other (OTH) AF: 0.0000920 AC: 2 AN: 21748

⚠️ 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 Cov.: 27

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

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

Other links and lift over

dbSNP: rs376183132; hg19: chr12-7169411;