15-78105888-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006383.4(CIB2):c.393G>A(p.Thr131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,614,138 control chromosomes in the GnomAD database, including 2,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (301 hom., cov: 32)
  • Exomes 𝑓: 0.044 (2381 hom.)
• Consequence: CIB2 NM_006383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.27

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 15-78105888-C-T is Benign according to our data. Variant chr15-78105888-C-T is described in ClinVar as [Benign]. Clinvar id is 226516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIB2	NM_006383.4	c.393G>A	p.Thr131=	synonymous_variant	5/6	ENST00000258930.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIB2	ENST00000258930.8	c.393G>A	p.Thr131=	synonymous_variant	5/6	1	NM_006383.4	P1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7774 AN: 152144 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0588

GnomAD3 exomes AF: 0.0503 AC: 12660 AN: 251446 Hom.: 673 AF XY: 0.0557 AC XY: 7566 AN XY: 135890

Gnomad AFR exome AF: 0.0827

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0599

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0443 AC: 64717 AN: 1461876 Hom.: 2381 Cov.: 33 AF XY: 0.0475 AC XY: 34573 AN XY: 727238

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.0567

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0370

Gnomad4 OTH exome AF: 0.0504

GnomAD4 genome AF: 0.0510 AC: 7769 AN: 152262 Hom.: 301 Cov.: 32 AF XY: 0.0510 AC XY: 3800 AN XY: 74446

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0357

Gnomad4 OTH AF: 0.0582

Alfa AF: 0.0353 Hom.: 66

Bravo AF: 0.0514

Asia WGS AF: 0.0870 AC: 303 AN: 3478

EpiCase AF: 0.0426

EpiControl AF: 0.0427

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr131Thr in exon 5 of CIB2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 7.6% (335/4392) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34057735). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.96
Dann	Benign	0.85

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

Other links and lift over

dbSNP: rs34057735; hg19: chr15-78398230; COSMIC: COSV51948507; COSMIC: COSV51948507;