dbSNP rs77370542: CIB2:p.Ser101Ser (chr15-78109278-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006383.4(CIB2):c.303G>A(p.Ser101Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,609,416 control chromosomes in the GnomAD database, including 1,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 77 hom., cov: 29)

Exomes 𝑓: 0.033 ( 939 hom. )

Consequence

CIB2
NM_006383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.117

Publications

5 publications found

Variant links:

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

CIB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 15-78109278-C-T is Benign according to our data. Variant chr15-78109278-C-T is described in ClinVar as Benign. ClinVar VariationId is 226515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.117 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (3621/151658) while in subpopulation NFE AF = 0.0364 (2470/67894). AF 95% confidence interval is 0.0352. There are 77 homozygotes in GnomAd4. There are 1760 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 77 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIB2	NM_006383.4	MANE Select	c.303G>A	p.Ser101Ser	synonymous	Exon 4 of 6	NP_006374.1	O75838-1
CIB2	NM_001301224.2		c.318G>A	p.Ser106Ser	synonymous	Exon 3 of 5	NP_001288153.1
CIB2	NM_001271888.2		c.174G>A	p.Ser58Ser	synonymous	Exon 3 of 5	NP_001258817.1	O75838-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIB2	ENST00000258930.8	TSL:1 MANE Select	c.303G>A	p.Ser101Ser	synonymous	Exon 4 of 6	ENSP00000258930.3	O75838-1
CIB2	ENST00000539011.5	TSL:1	c.174G>A	p.Ser58Ser	synonymous	Exon 3 of 5	ENSP00000442459.1	O75838-3
CIB2	ENST00000958911.1		c.300G>A	p.Ser100Ser	synonymous	Exon 4 of 6	ENSP00000628970.1

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3622

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00672

Gnomad AMI

AF:

0.0562

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.00629

Gnomad FIN

AF:

0.0498

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0241

GnomAD2 exomes

AF:

0.0246

AC:

6189

AN:

251278

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.0447

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0333

AC:

48601

AN:

1457758

Hom.:

939

Cov.:

AF XY:

0.0326

AC XY:

23607

AN XY:

725088

show subpopulations

African (AFR)

AF:

0.00512

AC:

170

AN:

33208

American (AMR)

AF:

0.0132

AC:

588

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26002

East Asian (EAS)

AF:

0.000711

AC:

AN:

39406

South Asian (SAS)

AF:

0.00735

AC:

633

AN:

86166

European-Finnish (FIN)

AF:

0.0439

AC:

2334

AN:

53200

Middle Eastern (MID)

AF:

0.00646

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0386

AC:

42773

AN:

1109330

Other (OTH)

AF:

0.0286

AC:

1720

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

2500

5000

7501

10001

12501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1590

3180

4770

6360

7950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0239

AC:

3621

AN:

151658

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1760

AN XY:

74082

show subpopulations

African (AFR)

AF:

0.00670

AC:

277

AN:

41324

American (AMR)

AF:

0.0112

AC:

170

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.000585

AC:

AN:

5132

South Asian (SAS)

AF:

0.00630

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.0498

AC:

524

AN:

10526

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0364

AC:

2470

AN:

67894

Other (OTH)

AF:

0.0238

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

151

302

452

603

754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0299

Hom.:

Bravo

AF:

0.0208

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0357

EpiControl

AF:

0.0330

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_noAF

Benign

-0.23

CADD

Benign

6.5

(source)

DANN

Benign

0.92

PhyloP100

-0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over