NM_006383.4:c.543-172A>G

Variant names:

• chr15-78105504-T-C
• rs7164338
• NM_006383.4:c.543-172A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006383.4(CIB2):​c.543-172A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,493,778 control chromosomes in the GnomAD database, including 49,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3871 hom., cov: 32)
  • Exomes 𝑓: 0.26 (45554 hom.)
• Consequence: CIB2 NM_006383.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.771
• Publications: 4 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, 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=-0.85).
• BP6: Variant 15-78105504-T-C is Benign according to our data. Variant chr15-78105504-T-C is described in ClinVar as Benign. ClinVar VariationId is 1245883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIB2	NM_006383.4	c.543-172A>G		intron_variant	Intron 5 of 5	ENST00000258930.8	NP_006374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIB2	ENST00000258930.8	c.543-172A>G		intron_variant	Intron 5 of 5	1	NM_006383.4	ENSP00000258930.3

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31981 AN: 151926 Hom.: 3876 Cov.: 32

Gnomad AFR AF: 0.0871

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.257 AC: 345243 AN: 1341734 Hom.: 45554 Cov.: 34 AF XY: 0.256 AC XY: 168138 AN XY: 656852

African (AFR) AF: 0.0820 AC: 2480 AN: 30254

American (AMR) AF: 0.205 AC: 6073 AN: 29624

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 6321 AN: 21336

East Asian (EAS) AF: 0.183 AC: 6482 AN: 35408

South Asian (SAS) AF: 0.192 AC: 13555 AN: 70574

European-Finnish (FIN) AF: 0.339 AC: 13255 AN: 39056

Middle Eastern (MID) AF: 0.252 AC: 962 AN: 3820

European-Non Finnish (NFE) AF: 0.267 AC: 282232 AN: 1056102

Other (OTH) AF: 0.250 AC: 13883 AN: 55560

GnomAD4 genome AF: 0.210 AC: 31972 AN: 152044 Hom.: 3871 Cov.: 32 AF XY: 0.213 AC XY: 15848 AN XY: 74308

African (AFR) AF: 0.0869 AC: 3606 AN: 41498

American (AMR) AF: 0.199 AC: 3045 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3468

East Asian (EAS) AF: 0.170 AC: 877 AN: 5156

South Asian (SAS) AF: 0.179 AC: 861 AN: 4822

European-Finnish (FIN) AF: 0.340 AC: 3602 AN: 10586

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18206 AN: 67922

Other (OTH) AF: 0.224 AC: 473 AN: 2108

Alfa AF: 0.245 Hom.: 792

Bravo AF: 0.196

Asia WGS AF: 0.165 AC: 576 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.77
Mutation Taster		=99/1	polymorphism (auto)

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: rs7164338; hg19: chr15-78397846;