rs145415848

chr15-78111171-C-Gchr15-78111171-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_006383.4(CIB2):c.192G>C(p.Glu64Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E64E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CIB2 NM_006383.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Calcium and integrin-binding family member 2 (size 186) in uniprot entity CIB2_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_006383.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-78111171-C-G is Pathogenic according to our data. Variant chr15-78111171-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 39688.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-78111171-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIB2	NM_006383.4	c.192G>C	p.Glu64Asp	missense_variant	3/6	ENST00000258930.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIB2	ENST00000258930.8	c.192G>C	p.Glu64Asp	missense_variant	3/6	1	NM_006383.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251356 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Usher syndrome type 1J Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2012	- -

Usher syndrome type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.054	T;D;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.84
MutPred		0.57		Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);.;.;
MVP		0.89
MPC		0.22
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.75
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs145415848; hg19: chr15-78403513;