dbSNP rs752972118: CIB3:p.Asp45Gly (chr19-16169694-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_054113.4(CIB3):c.134A>G(p.Asp45Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D45A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CIB3
NM_054113.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.10

Publications

0 publications found

Variant links:

Genes affected

CIB3 (HGNC:24580): (calcium and integrin binding family member 3) This gene product shares a high degree of sequence similarity with DNA-dependent protein kinase catalytic subunit-interacting protein 2 in human and mouse, and like them may bind the catalytic subunit of DNA-dependent protein kinases. The exact function of this gene is not known. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CIB3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIB3	NM_054113.4 link	c.134A>G	p.Asp45Gly	missense_variant	Exon 3 of 6	ENST00000269878.8	NP_473454.1	Q96Q77-1
CIB3	NM_001300922.2 link	c.52-1410A>G		intron_variant	Intron 1 of 3		NP_001287851.1	Q96Q77-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CIB3	ENST00000269878.8 link	c.134A>G	p.Asp45Gly	missense_variant	Exon 3 of 6	1	NM_054113.4	ENSP00000269878.3	Q96Q77-1
CIB3	ENST00000597251.5 link	n.115A>G		non_coding_transcript_exon_variant	Exon 3 of 6	1		ENSP00000470250.1	M0QZ29
CIB3	ENST00000379859.7 link	c.52-1410A>G		intron_variant	Intron 1 of 3	1		ENSP00000369188.3	Q96Q77-2
CIB3	ENST00000541493.1 link	n.86+3468A>G		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726992

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111688

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

0.18

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

PhyloP100

6.1

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.39

Sift

Benign

0.032

Sift4G

Uncertain

0.028

Polyphen

0.82

Vest4

0.72

MutPred

0.47

Gain of helix (P = 0.0022);

MVP

0.75

MPC

0.12

ClinPred

0.98

GERP RS

4.9

Varity_R

0.44

gMVP

0.79

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over