chr1-22644031-T-C

Position:

chr1-22644031-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_172369.5(C1QC):c.8T>C(p.Val3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,590,898 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 10 hom. )

Consequence

C1QC
NM_172369.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0800

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068438947).

BP6

Variant 1-22644031-T-C is Benign according to our data. Variant chr1-22644031-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1164154.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
C1QC	NM_172369.5 linkuse as main transcript	c.8T>C	p.Val3Ala	missense_variant	2/3	ENST00000374640.9	NP_758957.2
C1QC	NM_001114101.3 linkuse as main transcript	c.8T>C	p.Val3Ala	missense_variant	2/3		NP_001107573.1
C1QC	NM_001347619.2 linkuse as main transcript	c.8T>C	p.Val3Ala	missense_variant	2/3		NP_001334548.1
C1QC	NM_001347620.2 linkuse as main transcript	c.-87+317T>C		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.8T>C	p.Val3Ala	missense_variant	2/3	1	NM_172369.5	ENSP00000363771	P1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

151744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00521

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00111

AC:

233

AN:

209392

Hom.:

AF XY:

0.00149

AC XY:

168

AN XY:

112558

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00847

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000578

GnomAD4 exome

AF:

0.000503

AC:

724

AN:

1439034

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

505

AN XY:

713302

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000977

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00761

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000390

Gnomad4 OTH exome

AF:

0.000504

GnomAD4 genome

AF:

0.000257

AC:

AN:

151864

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00542

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000946

AC:

114

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	C1QC: BP4 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	- -

C1Q deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jan 27, 2022

C1QC NM_172369.4 exon 2 p.Val3Ala (c.8T>C): This variant has been reported in the literature in at least 1 individual with very early onset inflammatory bowel disease (VEO-IBD) (Kelsen 2015 PMID:26193622). This variant is present in 0.8% (218/25750) of South Asian alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-22970524-T-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:1164154). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.0

DANN

Benign

0.78

DEOGEN2

Benign

0.078

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.17

.;.;T

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.078

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.015

B;B;B

Vest4

0.10

MVP

0.74

MPC

0.38

ClinPred

0.017

GERP RS

0.55

Varity_R

0.033

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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