1-22659539-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378156.1(C1QB):c.77A>G(p.Gln26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q26H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: C1QB NM_001378156.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

Genes affected

C1QB (HGNC:1242): (complement C1q B chain) This gene encodes the B-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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36017746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QB	NM_001378156.1	c.77A>G	p.Gln26Arg	missense_variant	2/3	ENST00000509305.6
C1QB	NM_000491.5	c.83A>G	p.Gln28Arg	missense_variant	2/3
C1QB	NM_001371184.3	c.77A>G	p.Gln26Arg	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QB	ENST00000509305.6	c.77A>G	p.Gln26Arg	missense_variant	2/3	1	NM_001378156.1	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251246 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727212

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the C1QB protein (p.Gln28Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with C1QB-related conditions. 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.47	T;T;T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.038	D;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.68	.;.;.;P
Vest4		0.38, 0.39
MutPred		0.42		.;.;.;Gain of solvent accessibility (P = 0.0584);
MVP		0.90
MPC		0.59
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.53

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: rs1167283790; hg19: chr1-22986032;