chr12-7062107-T-TAAAA

Variant names:

• chr12-7062107-T-TAAAA
• rs376183132
• NM_001734.5:c.5+201_5+204dupAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001734.5(C1S):​c.5+201_5+204dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 387,446 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: 0.0000026 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+201_5+204dupAAAA		intron	N/A	NP_001725.1	P09871
	C1S	NM_201442.4		c.5+201_5+204dupAAAA		intron	N/A	NP_958850.1	P09871
	C1S	NM_001346850.2		c.-289+201_-289+204dupAAAA		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+201_5+204dupAAAA		intron	N/A	ENSP00000354057.5	P09871
	C1S	ENST00000328916.7	TSL:1	c.5+201_5+204dupAAAA		intron	N/A	ENSP00000328173.3	P09871
	C1S	ENST00000402681.7	TSL:1	c.-289+201_-289+204dupAAAA		intron	N/A	ENSP00000384171.3	F8WCZ6

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000258 AC: 1 AN: 387446 Hom.: 0 Cov.: 0 AF XY: 0.00000480 AC XY: 1 AN XY: 208516

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

African (AFR) AF: 0.00 AC: 0 AN: 10548

American (AMR) AF: 0.00 AC: 0 AN: 17096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11962

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 43126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22814

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

European-Non Finnish (NFE) AF: 0.00000428 AC: 1 AN: 233736

Other (OTH) AF: 0.00 AC: 0 AN: 21754

⚠️ 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

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;