dbSNP rs146998562: C1QC:p.Tyr33* (chr1-22644122-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_172369.5(C1QC):c.99C>A(p.Tyr33*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y33Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

C1QC
NM_172369.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.215

Publications

0 publications found

Variant links:

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

C1QC links:

ENSG00000289692 (HGNC:):

ENSG00000289692 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.866 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QC	NM_172369.5	MANE Select	c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	NP_758957.2	P02747
C1QC	NM_001114101.3		c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	NP_001107573.1	P02747
C1QC	NM_001347619.2		c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	NP_001334548.1	P02747

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QC	ENST00000374640.9	TSL:1 MANE Select	c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	ENSP00000363771.4	P02747
C1QC	ENST00000374637.1	TSL:3	c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	ENSP00000363768.1	P02747
C1QC	ENST00000374639.7	TSL:2	c.99C>A	p.Tyr33*	stop_gained	Exon 2 of 3	ENSP00000363770.3	P02747

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431234

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33260

American (AMR)

AF:

0.00

AC:

AN:

38598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25418

East Asian (EAS)

AF:

0.00

AC:

AN:

38746

South Asian (SAS)

AF:

0.00

AC:

AN:

81468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097750

Other (OTH)

AF:

0.00

AC:

AN:

59388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.17

PhyloP100

-0.21

Vest4

0.78

GERP RS

-2.4

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=7/193

disease causing (fs/PTC)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over