15-78109284-G-C

Variant names:

• chr15-78109284-G-C
• rs370965183
• NM_006383.4:c.297C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_006383.4(CIB2):​c.297C>G​(p.Cys99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C99R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CIB2 NM_006383.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.137
• Publications: 20 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 15-78109284-G-C is Pathogenic according to our data. Variant chr15-78109284-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39686.Status of the report is no_assertion_criteria_provided, 0 stars.

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.297C>G	p.Cys99Trp	missense	Exon 4 of 6	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.312C>G	p.Cys104Trp	missense	Exon 3 of 5	NP_001288153.1
	CIB2	NM_001271888.2		c.168C>G	p.Cys56Trp	missense	Exon 3 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.297C>G	p.Cys99Trp	missense	Exon 4 of 6	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.168C>G	p.Cys56Trp	missense	Exon 3 of 5	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.294C>G	p.Cys98Trp	missense	Exon 4 of 6	ENSP00000628970.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 48 (1)
1	-	-	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.14
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.74
MutPred		0.61		Loss of catalytic residue at S101 (P = 0.0595)
MVP		0.65
MPC		0.87
ClinPred		0.93	D
GERP RS		-3.7
Varity_R		0.71
gMVP		0.87
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs370965183; hg19: chr15-78401626;