1-22644031-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0800

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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: {Benign=1, Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QC	NM_172369.5	c.8T>C	p.Val3Ala	missense_variant	2/3	ENST00000374640.9
C1QC	NM_001114101.3	c.8T>C	p.Val3Ala	missense_variant	2/3
C1QC	NM_001347619.2	c.8T>C	p.Val3Ala	missense_variant	2/3
C1QC	NM_001347620.2	c.-87+317T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QC	ENST00000374640.9	c.8T>C	p.Val3Ala	missense_variant	2/3	1	NM_172369.5	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151744 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00149 AC XY: 168 AN XY: 112558

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.: 10 Cov.: 31 AF XY: 0.000708 AC XY: 505 AN XY: 713302

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: 39 AN: 151864 Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 29 AN XY: 74250

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.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000946 AC: 114

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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

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	T
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	N
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs367838299; hg19: chr1-22970524;