chr1-22644037-C-G

Position:

chr1-22644037-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_172369.5(C1QC):c.14C>G(p.Pro5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

C1QC
NM_172369.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.353

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:

ENSG00000289692 (HGNC:):

ENSG00000289692 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.116781175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1QC	NM_172369.5 link	c.14C>G	p.Pro5Arg	missense_variant	2/3	ENST00000374640.9	NP_758957.2	P02747A0A024RAA7
C1QC	NM_001114101.3 link	c.14C>G	p.Pro5Arg	missense_variant	2/3		NP_001107573.1	P02747A0A024RAA7
C1QC	NM_001347619.2 link	c.14C>G	p.Pro5Arg	missense_variant	2/3		NP_001334548.1	P02747A0A024RAA7
C1QC	NM_001347620.2 link	c.-87+323C>G		intron_variant			NP_001334549.1	A0A8Q3SIZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1QC	ENST00000374640.9 link	c.14C>G	p.Pro5Arg	missense_variant	2/3	1	NM_172369.5	ENSP00000363771.4		P02747
ENSG00000289692	ENST00000695747.1 link	c.599C>G	p.Pro200Arg	missense_variant	5/5			ENSP00000512140.1		A0A8Q3SI62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000484

AC:

AN:

206406

Hom.:

AF XY:

0.00000902

AC XY:

AN XY:

110836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000342

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000348

AC:

AN:

1437526

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

712356

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000247

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:

0.00000272

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 25, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. This variant has not been reported in the literature in individuals affected with C1QC-related conditions. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the C1QC protein (p.Pro5Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 17, 2023	BP4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.45

DANN

Benign

0.96

DEOGEN2

Benign

0.088

T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.37

.;.;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.67

N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.016

D;D;D

Sift4G

Benign

0.41

T;T;T

Polyphen

0.089

B;B;B

Vest4

0.079

MutPred

0.26

Gain of methylation at P5 (P = 0.0205);Gain of methylation at P5 (P = 0.0205);Gain of methylation at P5 (P = 0.0205);

MVP

0.73

MPC

0.42

ClinPred

0.039

GERP RS

2.4

Varity_R

0.036

gMVP

0.35

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