rs10456

Positions:

• chr15-78105804-G-A
• chr15-78105804-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006383.4(CIB2):​c.477C>T​(p.Asp159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,614,016 control chromosomes in the GnomAD database, including 44,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3096 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41582 hom.)
• Consequence: CIB2 NM_006383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.392

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-78105804-G-A is Benign according to our data. Variant chr15-78105804-G-A is described in ClinVar as [Benign]. Clinvar id is 226517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.392 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIB2	NM_006383.4	c.477C>T	p.Asp159=	synonymous_variant	5/6	ENST00000258930.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIB2	ENST00000258930.8	c.477C>T	p.Asp159=	synonymous_variant	5/6	1	NM_006383.4	P1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28251 AN: 152058 Hom.: 3099 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.204 AC: 51300 AN: 251430 Hom.: 5990 AF XY: 0.207 AC XY: 28103 AN XY: 135882

Gnomad AFR exome AF: 0.0731

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.0177

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.233 AC: 339996 AN: 1461840 Hom.: 41582 Cov.: 35 AF XY: 0.231 AC XY: 168166 AN XY: 727224

Gnomad4 AFR exome AF: 0.0728

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.186 AC: 28240 AN: 152176 Hom.: 3096 Cov.: 32 AF XY: 0.187 AC XY: 13880 AN XY: 74396

Gnomad4 AFR AF: 0.0776

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.193

Alfa AF: 0.231 Hom.: 5367

Bravo AF: 0.171

Asia WGS AF: 0.0960 AC: 334 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.245

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp159Asp 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 24.4% (2095/8586) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10456). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.26
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10456; hg19: chr15-78398146; COSMIC: COSV51948497; COSMIC: COSV51948497;