15-78105319-G-A

Position:

chr15-78105319-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_006383.4(CIB2):c.556C>T(p.Arg186Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CIB2
NM_006383.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2

Conservation

PhyloP100: 3.28

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 links:

CIB2 (HGNC:):

CIB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Calcium and integrin-binding family member 2 (size 186) in uniprot entity CIB2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_006383.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-78105319-G-A is Pathogenic according to our data. Variant chr15-78105319-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499480.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=5}. Variant chr15-78105319-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.31788698). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIB2	NM_006383.4 linkuse as main transcript	c.556C>T	p.Arg186Trp	missense_variant	6/6	ENST00000258930.8	NP_006374.1	O75838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIB2	ENST00000258930.8 linkuse as main transcript	c.556C>T	p.Arg186Trp	missense_variant	6/6	1	NM_006383.4	ENSP00000258930.3		O75838-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251128

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000204

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the CIB2 protein (p.Arg186Trp). This variant is present in population databases (rs370359511, gnomAD 0.05%). This missense change has been observed in individuals with non-syndromic sensorineural deafness (PMID: 26426422, 29112224, 34837038). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499480). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CIB2 function (PMID: 26426422, 28663585). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2024	Published functional studies suggest the p.(R186W) variant results in the loss of calcium sequestering ability relative to wild-type (PMID: 26426422); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663585, 30174586, 26426422, 29112224, 35440622, 26214305, 35408910, 34837038, 36936795, 36224384, 36223766, 37461484) -

Autosomal recessive nonsyndromic hearing loss 48

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Wonkam Laboratory, Johns Hopkins University	Jan 06, 2024	The variant NM_001271889.2 c.409C>T is located in a mutational hot spot and/or critical and well-established functional domain of PCDH15 (PM1), Absent from controls (or at extremely low frequency if recessive) in gnomAdv4.1.0 (PM2), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2) -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jan 31, 2021	- -

Usher syndrome

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 21, 2022

Variant summary: CIB2 c.556C>T (p.Arg186Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251128 control chromosomes. c.556C>T has been reported in the literature as a homozygous genotype in two affected probands each from at-least two distinct families (Carribean and Yoruba Nigerian) with features of Non-syndromic hearing loss (NSHL) and secondary citations by others (example, Patel_2015, Delio_2015, Booth_2019, Adeyemo_2022). Biallelic loss of function variants in CIB2 have been reported to cause autosomal recessive non-syndromic hearing loss (ARNSHL) and not Usher syndrome (USH) (Booth_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported, although one study reported p.Arg186Trp mutation affects the calcium binding affinity of CIB2 but did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia (Patel_2015). Another study reported this variant as not having notable changes in CIB2 intracellular localization in CHO-K1 cells and no effect on interactions with TMC1 in vitro (Giese_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3, P/LP, n=2). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Childhood onset hearing loss

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

PS3_supporting, PM1, PM2_supporting, PM3_supporting, PP1_moderate / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

May 01, 2024

The CIB2:NM_006383.3:c.556C>T variant has extremely low frequency in gnomAD population databases (PM2), is associated with a recessive disorder, detected in trans with a pathogenic variant, in homozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), reported in ClkniVar in affected individuals (PP5). Here it was found in homozygosis in two affected siblings born from consanguineous marriage. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 22, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p. Arg186Trp variant in CIB2 has been previously reported in the homozygous state in 1 Caribbean Hispanic individual with hearing loss and segregated with disease in 1 affected sibling, also homozygous for the variant (Patel 2015). This variant has been identified in 0.05% (13/24914) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is present in ClinVar (Variation ID 499480). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, PP1, PP3, PM3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Uncertain

-0.016

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.59

MVP

0.96

MPC

0.80

ClinPred

0.86

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over