chr1-22644027-G-A

Position:

chr1-22644027-G-A

Variant summary

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

The NM_172369.5(C1QC):c.4G>A(p.Asp2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,592,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

C1QC
NM_172369.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

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 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=0.1676242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
C1QC	NM_172369.5 linkuse as main transcript	c.4G>A	p.Asp2Asn	missense_variant	2/3	ENST00000374640.9	NP_758957.2
C1QC	NM_001114101.3 linkuse as main transcript	c.4G>A	p.Asp2Asn	missense_variant	2/3		NP_001107573.1
C1QC	NM_001347619.2 linkuse as main transcript	c.4G>A	p.Asp2Asn	missense_variant	2/3		NP_001334548.1
C1QC	NM_001347620.2 linkuse as main transcript	c.-87+313G>A		intron_variant			NP_001334549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1QC	ENST00000374640.9 linkuse as main transcript	c.4G>A	p.Asp2Asn	missense_variant	2/3	1	NM_172369.5	ENSP00000363771	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152166

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000473

AC:

AN:

211392

Hom.:

AF XY:

0.00000880

AC XY:

AN XY:

113642

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:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000736

AC:

106

AN:

1440082

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

713910

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:

0.0000943

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2021

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2 of the C1QC protein (p.Asp2Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with C1QC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.085

T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.52

.;.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.60

P;P;P

Vest4

0.12

MutPred

0.42

Loss of phosphorylation at S6 (P = 0.1494);Loss of phosphorylation at S6 (P = 0.1494);Loss of phosphorylation at S6 (P = 0.1494);

MVP

0.91

MPC

1.0

ClinPred

0.40

GERP RS

5.5

Varity_R

0.090

gMVP

0.38

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