chr15-78105126-G-C

Variant names:

• chr15-78105126-G-C
• rs11633444
• NM_006383.4:c.*185C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006383.4(CIB2):​c.*185C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 772,342 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (19 hom., cov: 32)
  • Exomes 𝑓: 0.021 (198 hom.)
• Consequence: CIB2 NM_006383.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.493
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-78105126-G-C is Benign according to our data. Variant chr15-78105126-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1179220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2373/152118) while in subpopulation NFE AF = 0.0239 (1626/67964). AF 95% confidence interval is 0.023. There are 19 homozygotes in GnomAd4. There are 1096 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,Unknown gene

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.*185C>G		3_prime_UTR	Exon 6 of 6	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.*185C>G		3_prime_UTR	Exon 5 of 5	NP_001288153.1
	CIB2	NM_001271888.2		c.*185C>G		3_prime_UTR	Exon 5 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.*185C>G		3_prime_UTR	Exon 6 of 6	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.*185C>G		3_prime_UTR	Exon 5 of 5	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.*185C>G		3_prime_UTR	Exon 6 of 6	ENSP00000628970.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2373 AN: 152000 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0210 AC: 12995 AN: 620224 Hom.: 198 Cov.: 8 AF XY: 0.0208 AC XY: 6660 AN XY: 319798

African (AFR) AF: 0.00448 AC: 69 AN: 15404

American (AMR) AF: 0.0169 AC: 345 AN: 20380

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 402 AN: 14550

East Asian (EAS) AF: 0.0000328 AC: 1 AN: 30486

South Asian (SAS) AF: 0.0169 AC: 847 AN: 50158

European-Finnish (FIN) AF: 0.00555 AC: 171 AN: 30838

Middle Eastern (MID) AF: 0.0339 AC: 83 AN: 2448

European-Non Finnish (NFE) AF: 0.0244 AC: 10374 AN: 425214

Other (OTH) AF: 0.0229 AC: 703 AN: 30746

GnomAD4 genome AF: 0.0156 AC: 2373 AN: 152118 Hom.: 19 Cov.: 32 AF XY: 0.0147 AC XY: 1096 AN XY: 74372

African (AFR) AF: 0.00429 AC: 178 AN: 41516

American (AMR) AF: 0.0194 AC: 297 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4820

European-Finnish (FIN) AF: 0.00387 AC: 41 AN: 10582

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1626 AN: 67964

Other (OTH) AF: 0.0223 AC: 47 AN: 2110

Alfa AF: 0.0104 Hom.: 1

Bravo AF: 0.0174

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.72
PhyloP100		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11633444; hg19: chr15-78397468;