rs115035173

Variant names:

• chr15-78105468-G-A
• rs115035173
• NM_006383.4:c.543-136C>T

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.543-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,540,852 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: CIB2 NM_006383.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.530
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 15-78105468-G-A is Benign according to our data. Variant chr15-78105468-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1191815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1631/152304) while in subpopulation AFR AF = 0.0369 (1535/41560). AF 95% confidence interval is 0.0354. There are 34 homozygotes in GnomAd4. There are 780 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.543-136C>T		intron	N/A	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.558-136C>T		intron	N/A	NP_001288153.1
	CIB2	NM_001271888.2		c.414-136C>T		intron	N/A	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.543-136C>T		intron	N/A	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.414-136C>T		intron	N/A	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.540-136C>T		intron	N/A	ENSP00000628970.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1616 AN: 152186 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00106 AC: 1476 AN: 1388548 Hom.: 29 Cov.: 30 AF XY: 0.000932 AC XY: 638 AN XY: 684454

African (AFR) AF: 0.0364 AC: 1140 AN: 31308

American (AMR) AF: 0.00319 AC: 110 AN: 34534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23968

East Asian (EAS) AF: 0.00 AC: 0 AN: 35998

South Asian (SAS) AF: 0.0000771 AC: 6 AN: 77816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47104

Middle Eastern (MID) AF: 0.00241 AC: 10 AN: 4158

European-Non Finnish (NFE) AF: 0.0000530 AC: 57 AN: 1076170

Other (OTH) AF: 0.00266 AC: 153 AN: 57492

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 152304 Hom.: 34 Cov.: 32 AF XY: 0.0105 AC XY: 780 AN XY: 74474

African (AFR) AF: 0.0369 AC: 1535 AN: 41560

American (AMR) AF: 0.00444 AC: 68 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00803 Hom.: 7

Bravo AF: 0.0129

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.98
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-0.53
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: rs115035173; hg19: chr15-78397810;