rs147222955

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_014008.5(CCDC22):c.1636G>A(p.Asp546Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00518 in 1,203,580 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,906 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., 89 hem., cov: 21)

Exomes 𝑓: 0.0053 ( 15 hom. 1817 hem. )

Consequence

CCDC22
NM_014008.5 missense, splice_region

Scores

Splicing: ADA: 0.9990

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.05

Publications

11 publications found

Variant links:

Genes affected

CCDC22 (HGNC:28909): (coiled-coil domain containing 22) This gene encodes a protein containing a coiled-coil domain. The encoded protein functions in the regulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) by interacting with COMMD (copper metabolism Murr1 domain-containing) proteins. The mouse orthologous protein has been shown to bind copines, which are calcium-dependent, membrane-binding proteins that may function in calcium signaling. This human gene has been identified as a novel candidate gene for syndromic X-linked intellectual disability. [provided by RefSeq, Aug 2013]

CCDC22 Gene-Disease associations (from GenCC):

Ritscher-Schinzel syndrome 2
Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Ritscher-Schinzel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CCDC22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant X-49249509-G-A is Benign according to our data. Variant chrX-49249509-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 89 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC22	NM_014008.5 link	c.1636G>A	p.Asp546Asn	missense_variant, splice_region_variant	Exon 15 of 17	ENST00000376227.4	NP_054727.1	O60826A0A024QZ03
CCDC22	XM_005272599.5 link	c.1633G>A	p.Asp545Asn	missense_variant, splice_region_variant	Exon 15 of 17		XP_005272656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4 link	c.1636G>A	p.Asp546Asn	missense_variant, splice_region_variant	Exon 15 of 17	1	NM_014008.5	ENSP00000365401.3		O60826

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

376

AN:

108215

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000843

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00110

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00206

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00593

Gnomad OTH

AF:

0.000693

GnomAD2 exomes

AF:

0.00350

AC:

641

AN:

183077

AF XY:

0.00363

show subpopulations

Gnomad AFR exome

AF:

0.000914

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00182

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00534

AC:

5854

AN:

1095319

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

1817

AN XY:

360837

show subpopulations

African (AFR)

AF:

0.000493

AC:

AN:

26348

American (AMR)

AF:

0.00151

AC:

AN:

35164

Ashkenazi Jewish (ASJ)

AF:

0.00393

AC:

AN:

19344

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00177

AC:

AN:

54101

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

40441

Middle Eastern (MID)

AF:

0.000727

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.00631

AC:

5302

AN:

839687

Other (OTH)

AF:

0.00503

AC:

231

AN:

45961

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

190

381

571

762

952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00347

AC:

376

AN:

108261

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

AN XY:

30917

show subpopulations

African (AFR)

AF:

0.000841

AC:

AN:

29731

American (AMR)

AF:

0.00110

AC:

AN:

9966

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

2605

East Asian (EAS)

AF:

0.00

AC:

AN:

3402

South Asian (SAS)

AF:

0.00206

AC:

AN:

2424

European-Finnish (FIN)

AF:

0.00218

AC:

AN:

5500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00593

AC:

310

AN:

52282

Other (OTH)

AF:

0.000684

AC:

AN:

1462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00438

Hom.:

207

Bravo

AF:

0.00296

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00699

AC:

ExAC

AF:

0.00394

AC:

479

EpiCase

AF:

0.00556

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 13, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Oct 16, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

PhyloP100

6.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.48

Sift

Benign

0.094

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.20

MVP

0.65

MPC

0.54

ClinPred

0.014

GERP RS

5.4

Varity_R

0.67

gMVP

0.76

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.080

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over