1-22659475-T-G

Variant names:

• chr1-22659475-T-G
• NM_001378156.1:c.13T>G

Variant summary

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

The NM_001378156.1(C1QB):​c.13T>G​(p.Trp5Gly) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.972

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]

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=0.27608296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QB	NM_001378156.1	c.13T>G	p.Trp5Gly	missense_variant	Exon 2 of 3	ENST00000509305.6	NP_001365085.1
C1QB	NM_000491.5	c.19T>G	p.Trp7Gly	missense_variant	Exon 2 of 3		NP_000482.3
C1QB	NM_001371184.3	c.13T>G	p.Trp5Gly	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.13T>G	p.Trp5Gly	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

Aug 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 7 of the C1QB protein (p.Trp7Gly). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.24
DANN	Benign	0.64
DEOGEN2	Benign	0.055	.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.34	T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	.;.;.;L
PhyloP100		-0.97
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.36	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.065	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.19, 0.17
MutPred		0.61		.;.;.;Gain of disorder (P = 0.0084);
MVP		0.86
MPC		0.83
ClinPred		0.049	T
GERP RS		-1.7
Varity_R		0.088
gMVP		0.73
Mutation Taster		=95/5	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

Publications

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Other links and lift over

hg19: chr1-22985968;