1-22659508-C-A

Variant names:

• chr1-22659508-C-A
• rs769378243
• NM_001378156.1:c.46C>A

Variant summary

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

The NM_001378156.1(C1QB):​c.46C>A​(p.Leu16Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QB NM_001378156.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200
• 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=0.29518247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QB	NM_001378156.1	c.46C>A	p.Leu16Ile	missense_variant	Exon 2 of 3	ENST00000509305.6	NP_001365085.1
C1QB	NM_000491.5	c.52C>A	p.Leu18Ile	missense_variant	Exon 2 of 3		NP_000482.3
C1QB	NM_001371184.3	c.46C>A	p.Leu16Ile	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.46C>A	p.Leu16Ile	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	.;T;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.45	T;T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	.;.;.;M
PhyloP100		-0.020
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.099	T;T;D;T
Sift4G	Uncertain	0.042	D;D;T;D
Polyphen		0.16	.;.;.;B
Vest4		0.34, 0.34
MutPred		0.62		.;.;.;Gain of catalytic residue at L18 (P = 0.0303);
MVP		0.87
MPC		1.4
ClinPred		0.10	T
GERP RS		1.7
Varity_R		0.065
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs769378243; hg19: chr1-22986001;