chr1-22659540-G-C

Variant names:

• chr1-22659540-G-C
• NM_001378156.1:c.78G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378156.1(C1QB):​c.78G>C​(p.Gln26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. Q26R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QB NM_001378156.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.818
• Publications: 0 publications found

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]

C1QB Gene-Disease associations (from GenCC):

• C1Q deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000308848 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3973289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QB	NM_001378156.1	c.78G>C	p.Gln26His	missense_variant	Exon 2 of 3	ENST00000509305.6	NP_001365085.1
C1QB	NM_000491.5	c.84G>C	p.Gln28His	missense_variant	Exon 2 of 3		NP_000482.3
C1QB	NM_001371184.3	c.78G>C	p.Gln26His	missense_variant	Exon 3 of 4		NP_001358113.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QB	ENST00000509305.6	c.78G>C	p.Gln26His	missense_variant	Exon 2 of 3	1	NM_001378156.1	ENSP00000423689.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 28 of the C1QB protein (p.Gln28His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with C1QB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2048113). 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 disruptive. 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	0.16
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	.;T;T;T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.1	.;.;.;M
PhyloP100		0.82
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.98	N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;T;D;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.94	.;.;.;P
Vest4		0.41, 0.38
MutPred		0.32		.;.;.;Loss of disorder (P = 0.0986);
MVP		0.92
MPC		0.98
ClinPred		0.36	T
GERP RS		1.5
Varity_R		0.060
gMVP		0.57
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr1-22986033;