NM_172369.5:c.212_213delCC

Variant names:

• chr1-22647255-ACC-A
• rs761681612
• NM_172369.5:c.212_213delCC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_172369.5(C1QC):​c.212_213delCC​(p.Pro71GlnfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P71P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: C1QC NM_172369.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.59
• Publications: 1 publications found

Genes affected

C1QC (HGNC:1245): (complement C1q C chain) This gene encodes the C-chain polypeptide of serum complement subcomponent C1q, which associates with C1r and C1s to yield the first component of the serum complement system. C1q is composed of 18 polypeptide chains which include 6 A-chains, 6 B-chains, and 6 C-chains. Each chain contains an N-terminal collagen-like region and a C-terminal C1q globular domain. C1q deficiency is associated with lupus erythematosus and glomerulonephritis. [provided by RefSeq, Dec 2016]

C1QC Gene-Disease associations (from GenCC):

• C1Q deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.713 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-22647255-ACC-A is Pathogenic according to our data. Variant chr1-22647255-ACC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3718107.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QC	NM_172369.5	MANE Select	c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	NP_758957.2
	C1QC	NM_001114101.3		c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	NP_001107573.1
	C1QC	NM_001347619.2		c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	NP_001334548.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QC	ENST00000374640.9	TSL:1 MANE Select	c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	ENSP00000363771.4
	C1QC	ENST00000374637.1	TSL:3	c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	ENSP00000363768.1
	C1QC	ENST00000374639.7	TSL:2	c.212_213delCC	p.Pro71GlnfsTer39	frameshift	Exon 3 of 3	ENSP00000363770.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457048 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725020

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151902 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74176

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	C1Q deficiency 3 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=21/179	disease causing

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: rs761681612; hg19: chr1-22973748;