rs752596663

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_172369.5(C1QC):c.490G>A(p.Gly164Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

C1QC
NM_172369.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
C1QC	NM_172369.5 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/3	ENST00000374640.9
C1QC	NM_001114101.3 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/3
C1QC	NM_001347619.2 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/3
C1QC	NM_001347620.2 linkuse as main transcript	c.223G>A	p.Gly75Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QC	ENST00000374640.9 linkuse as main transcript	c.490G>A	p.Gly164Ser	missense_variant	3/3	1	NM_172369.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000845

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

C1Q deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Jan 29, 2019

- -

C1Q deficiency 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 31, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 164 of the C1QC protein (p.Gly164Ser). This variant is present in population databases (rs752596663, gnomAD 0.004%). This missense change has been observed in individual(s) with C1QC-related conditions (PMID: 24157463). ClinVar contains an entry for this variant (Variation ID: 440743). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.98

MVP

0.95

MPC

1.0

ClinPred

1.0

GERP RS

4.7

Varity_R

0.89

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over