rs10456

Variant names:

• chr15-78105804-G-A
• rs10456
• NM_006383.4:c.477C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006383.4(CIB2):​c.477C>T​(p.Asp159Asp) 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
• Publications: 23 publications found

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
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 1

  Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006383.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIB2	NM_006383.4	MANE Select	c.477C>T	p.Asp159Asp	synonymous	Exon 5 of 6	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.492C>T	p.Asp164Asp	synonymous	Exon 4 of 5	NP_001288153.1
	CIB2	NM_001271888.2		c.348C>T	p.Asp116Asp	synonymous	Exon 4 of 5	NP_001258817.1	O75838-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIB2	ENST00000258930.8	TSL:1 MANE Select	c.477C>T	p.Asp159Asp	synonymous	Exon 5 of 6	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.348C>T	p.Asp116Asp	synonymous	Exon 4 of 5	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.474C>T	p.Asp158Asp	synonymous	Exon 5 of 6	ENSP00000628970.1

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

GnomAD2 exomes AF: 0.204 AC: 51300 AN: 251430 AF XY: 0.207

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 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

African (AFR) AF: 0.0728 AC: 2437 AN: 33480

American (AMR) AF: 0.166 AC: 7434 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7504 AN: 26136

East Asian (EAS) AF: 0.0224 AC: 888 AN: 39700

South Asian (SAS) AF: 0.162 AC: 14000 AN: 86256

European-Finnish (FIN) AF: 0.306 AC: 16317 AN: 53410

Middle Eastern (MID) AF: 0.221 AC: 1277 AN: 5768

European-Non Finnish (NFE) AF: 0.249 AC: 276624 AN: 1111974

Other (OTH) AF: 0.224 AC: 13515 AN: 60394

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

African (AFR) AF: 0.0776 AC: 3221 AN: 41528

American (AMR) AF: 0.165 AC: 2521 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1014 AN: 3470

East Asian (EAS) AF: 0.0228 AC: 118 AN: 5176

South Asian (SAS) AF: 0.152 AC: 733 AN: 4826

European-Finnish (FIN) AF: 0.303 AC: 3205 AN: 10586

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16803 AN: 67976

Other (OTH) AF: 0.193 AC: 408 AN: 2112

Alfa AF: 0.223 Hom.: 11843

Bravo AF: 0.171

Asia WGS AF: 0.0960 AC: 334 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.26
DANN	Benign	0.80
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10456; hg19: chr15-78398146; COSMIC: COSV51948497; COSMIC: COSV51948497;