Genetic Variant CIB3:p.Asp45Ala (chr19-16169694-T-G) – 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>C(p.Asp45Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CIB3
NM_054113.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

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, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIB3	NM_054113.4 link	c.134A>C	p.Asp45Ala	missense_variant	Exon 3 of 6	ENST00000269878.8	NP_473454.1	Q96Q77-1
CIB3	NM_001300922.2 link	c.52-1410A>C		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>C	p.Asp45Ala	missense_variant	Exon 3 of 6	1	NM_054113.4	ENSP00000269878.3	Q96Q77-1
CIB3	ENST00000597251.5 link	n.115A>C		non_coding_transcript_exon_variant	Exon 3 of 6	1		ENSP00000470250.1	M0QZ29
CIB3	ENST00000379859.7 link	c.52-1410A>C		intron_variant	Intron 1 of 3	1		ENSP00000369188.3	Q96Q77-2
CIB3	ENST00000541493.1 link	n.86+3468A>C		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250172

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726992

show subpopulations

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:

0.00

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:

0.0000117

AC:

AN:

1111688

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.134A>C (p.D45A) alteration is located in exon 3 (coding exon 3) of the CIB3 gene. This alteration results from a A to C substitution at nucleotide position 134, causing the aspartic acid (D) at amino acid position 45 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

0.18

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

PhyloP100

6.1

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.40

Sift

Benign

0.073

Sift4G

Uncertain

0.055

Polyphen

0.69

Vest4

0.68

MutPred

0.49

Gain of helix (P = 0.0022);

MVP

0.77

MPC

0.11

ClinPred

0.97

GERP RS

4.9

Varity_R

0.34

gMVP

0.79

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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19-16169694-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over