chr15-78105382-G-A

Variant names:

• chr15-78105382-G-A
• rs140416909
• NM_006383.4:c.543-50C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006383.4(CIB2):​c.543-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,612,542 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: CIB2 NM_006383.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.230
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-78105382-G-A is Benign according to our data. Variant chr15-78105382-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1207268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000696 (106/152272) while in subpopulation EAS AF = 0.0182 (94/5178). AF 95% confidence interval is 0.0152. There are 2 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.543-50C>T		intron	N/A	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.558-50C>T		intron	N/A	NP_001288153.1
	CIB2	NM_001271888.2		c.414-50C>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.543-50C>T		intron	N/A	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.414-50C>T		intron	N/A	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.540-50C>T		intron	N/A	ENSP00000628970.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152154 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00123 AC: 305 AN: 247796 AF XY: 0.00112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1460270 Hom.: 6 Cov.: 30 AF XY: 0.000472 AC XY: 343 AN XY: 726266

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.0105 AC: 417 AN: 39636

South Asian (SAS) AF: 0.00156 AC: 134 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111440

Other (OTH) AF: 0.000663 AC: 40 AN: 60306

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152272 Hom.: 2 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0182 AC: 94 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

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: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000914

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.6
DANN	Benign	0.69
PhyloP100		0.23
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: rs140416909; hg19: chr15-78397724;