17-5433026-T-G

Position:

• chr17-5433026-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001212.4(C1QBP):​c.838A>C​(p.Lys280Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QBP NM_001212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

C1QBP (HGNC:1243): (complement C1q binding protein) The human complement subcomponent C1q associates with C1r and C1s in order to yield the first component of the serum complement system. The protein encoded by this gene is known to bind to the globular heads of C1q molecules and inhibit C1 activation. This protein has also been identified as the p32 subunit of pre-mRNA splicing factor SF2, as well as a hyaluronic acid-binding protein. [provided by RefSeq, Jul 2008]

C1QBP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1QBP	NM_001212.4	c.838A>C	p.Lys280Gln	missense_variant	6/6	ENST00000225698.8	NP_001203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1QBP	ENST00000225698.8	c.838A>C	p.Lys280Gln	missense_variant	6/6	1	NM_001212.4	ENSP00000225698.4
C1QBP	ENST00000574444.5	c.526A>C	p.Lys176Gln	missense_variant	6/6	3		ENSP00000460308.1
C1QBP	ENST00000570805.1	c.526A>C	p.Lys176Gln	missense_variant	6/6	3		ENSP00000460638.1
C1QBP	ENST00000573204.1	n.*46A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2022

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 280 of the C1QBP protein (p.Lys280Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with C1QBP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.15
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.075	T;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.99	D;.;.
Vest4		0.46
MutPred		0.46		Loss of methylation at K280 (P = 0.0177);.;.;
MVP		0.41
MPC		0.89
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.68
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1916135673; hg19: chr17-5336346;