Genetic Variant NM_001378156.1:c.116C>A (chr1-22659578-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378156.1(C1QB):c.116C>A(p.Pro39Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P39L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

C1QB
NM_001378156.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

0 publications found

Variant links:

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)

C1QB links:

ENSG00000308848 (HGNC:):

ENSG00000308848 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QB	NM_001378156.1 link	c.116C>A	p.Pro39Gln	missense_variant	Exon 2 of 3	ENST00000509305.6	NP_001365085.1
C1QB	NM_000491.5 link	c.122C>A	p.Pro41Gln	missense_variant	Exon 2 of 3		NP_000482.3	P02746A0A024RAB9
C1QB	NM_001371184.3 link	c.116C>A	p.Pro39Gln	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 link	c.116C>A	p.Pro39Gln	missense_variant	Exon 2 of 3	1	NM_001378156.1	ENSP00000423689.1		D6R934

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

.;D;T;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

.;.;.;M

PhyloP100

2.8

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.33, 0.37

MutPred

0.36

.;.;.;Gain of relative solvent accessibility (P = 0.09);

MVP

0.98

MPC

1.3

ClinPred

0.94

GERP RS

3.7

Varity_R

0.28

gMVP

0.58

Mutation Taster

=48/52

disease causing

(source)

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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NM_001378156.1:c.116C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over