rs1281648597

Variant names:

• chr15-78105318-C-T
• rs1281648597
• NM_006383.4:c.557G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-78105318-C-T
• chr15-78105318-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_006383.4(CIB2):​c.557G>A​(p.Arg186Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CIB2 NM_006383.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.13
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-78105319-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499480.
• PP5: Variant 15-78105318-C-T is Pathogenic according to our data. Variant chr15-78105318-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505421.

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.557G>A	p.Arg186Gln	missense	Exon 6 of 6	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.572G>A	p.Arg191Gln	missense	Exon 5 of 5	NP_001288153.1
	CIB2	NM_001271888.2		c.428G>A	p.Arg143Gln	missense	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.557G>A	p.Arg186Gln	missense	Exon 6 of 6	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.428G>A	p.Arg143Gln	missense	Exon 5 of 5	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.554G>A	p.Arg185Gln	missense	Exon 6 of 6	ENSP00000628970.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251118 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461758 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.69	D
PhyloP100		4.1
PROVEAN	Uncertain	-2.8	D
Sift	Uncertain	0.0020	D
MVP		0.90
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1281648597; hg19: chr15-78397660; COSMIC: COSV51948655; COSMIC: COSV51948655;