NM_006383.4:c.523A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_006383.4(CIB2):c.523A>C(p.Lys175Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000558 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K175E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

CIB2
NM_006383.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:2B:4

Conservation

PhyloP100: 6.08

Publications

4 publications found

Variant links:

Genes affected

CIB2 (HGNC:24579): (calcium and integrin binding family member 2) The protein encoded by this gene is similar to that of KIP/CIB, calcineurin B, and calmodulin. The encoded protein is a calcium-binding regulatory protein that interacts with DNA-dependent protein kinase catalytic subunits (DNA-PKcs), and it is involved in photoreceptor cell maintenance. Mutations in this gene cause deafness, autosomal recessive, 48 (DFNB48), and also Usher syndrome 1J (USH1J). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CIB2 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1J
Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive nonsyndromic hearing loss 48
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 1
Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet

CIB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017278463).

BP6

Variant 15-78105758-T-G is Benign according to our data. Variant chr15-78105758-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 227251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000553 (808/1461860) while in subpopulation NFE AF = 0.000531 (591/1112002). AF 95% confidence interval is 0.000495. There are 0 homozygotes in GnomAdExome4. There are 390 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIB2	NM_006383.4 link	c.523A>C	p.Lys175Gln	missense_variant	Exon 5 of 6	ENST00000258930.8	NP_006374.1	O75838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIB2	ENST00000258930.8 link	c.523A>C	p.Lys175Gln	missense_variant	Exon 5 of 6	1	NM_006383.4	ENSP00000258930.3		O75838-1

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00395

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000748

AC:

188

AN:

251392

AF XY:

0.000765

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.000932

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000553

AC:

808

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

390

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00292

AC:

156

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000531

AC:

591

AN:

1112002

Other (OTH)

AF:

0.000530

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000604

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41570

American (AMR)

AF:

0.000588

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00395

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000471

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000955

AC:

116

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys175Gln in exon 5 of CIB2: This variant is not expected to have clinical si gnificance because it has been identified in several populations by the Exome Ag gregation Consortium, including 0.13% (85/66702) of European chromosomes and 0.2 3% (15/6568) of Finnish chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs200546031). -

CIB2-related disorder

Benign:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

0.066

B;.;.;.

Vest4

0.46

MVP

0.83

MPC

0.67

ClinPred

0.053

GERP RS

5.6

Varity_R

0.37

gMVP

0.48

Mutation Taster

=96/4

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over