rs141932061

Variant names:

• chr15-78105833-C-T
• rs141932061
• NM_006383.4:c.448G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-78105833-C-T
• chr15-78105833-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006383.4(CIB2):​c.448G>A​(p.Asp150Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,212 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: CIB2 NM_006383.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.09
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009683847).
• BP6: Variant 15-78105833-C-T is Benign according to our data. Variant chr15-78105833-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00292 (445/152344) while in subpopulation AFR AF = 0.00849 (353/41572). AF 95% confidence interval is 0.00776. There are 1 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.448G>A	p.Asp150Asn	missense	Exon 5 of 6	NP_006374.1	O75838-1
	CIB2	NM_001301224.2		c.463G>A	p.Asp155Asn	missense	Exon 4 of 5	NP_001288153.1
	CIB2	NM_001271888.2		c.319G>A	p.Asp107Asn	missense	Exon 4 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.448G>A	p.Asp150Asn	missense	Exon 5 of 6	ENSP00000258930.3	O75838-1
	CIB2	ENST00000539011.5	TSL:1	c.319G>A	p.Asp107Asn	missense	Exon 4 of 5	ENSP00000442459.1	O75838-3
	CIB2	ENST00000958911.1		c.445G>A	p.Asp149Asn	missense	Exon 5 of 6	ENSP00000628970.1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00200 AC: 503 AN: 251478 AF XY: 0.00222

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00102 AC: 1492 AN: 1461868 Hom.: 14 Cov.: 33 AF XY: 0.00127 AC XY: 920 AN XY: 727236

African (AFR) AF: 0.00896 AC: 300 AN: 33478

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00916 AC: 790 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1111994

Other (OTH) AF: 0.00134 AC: 81 AN: 60392

GnomAD4 genome AF: 0.00292 AC: 445 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74482

African (AFR) AF: 0.00849 AC: 353 AN: 41572

American (AMR) AF: 0.00229 AC: 35 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.00340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00820 AC: 36

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00218 AC: 265

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	CIB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.65	N
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Benign	0.079	T
Sift4G	Benign	0.16	T
Polyphen		0.021	B
Vest4		0.19
MVP		0.82
MPC		0.21
ClinPred		0.028	T
GERP RS		5.2
Varity_R		0.31
gMVP		0.37
Mutation Taster		=99/1	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: rs141932061; hg19: chr15-78398175;