Genetic Variant NM_001378156.1:c.36G>A (chr1-22659498-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001378156.1(C1QB):c.36G>A(p.Met12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

C1QB
NM_001378156.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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 links:

ENSG00000308848 (HGNC:):

ENSG00000308848 links:

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ACMG classification

Classification was made for transcript

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=0.28534204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QB	NM_001378156.1 link	c.36G>A	p.Met12Ile	missense_variant	Exon 2 of 3	ENST00000509305.6	NP_001365085.1
C1QB	NM_000491.5 link	c.42G>A	p.Met14Ile	missense_variant	Exon 2 of 3		NP_000482.3	P02746A0A024RAB9
C1QB	NM_001371184.3 link	c.36G>A	p.Met12Ile	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.36G>A	p.Met12Ile	missense_variant	Exon 2 of 3	1	NM_001378156.1	ENSP00000423689.1		D6R934

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251386

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

C1Q deficiency 2

Uncertain:1

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.014

.;T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.42

T;T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.0

.;.;.;L

PhyloP100

1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.17

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.25

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.0010

.;.;.;B

Vest4

0.25, 0.23

MutPred

0.57

.;.;.;Gain of catalytic residue at L19 (P = 0.1269);

MVP

0.90

MPC

0.51

ClinPred

0.064

GERP RS

3.6

Varity_R

0.16

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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NM_001378156.1:c.36G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over