rs199809018

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.715G>A(p.Glu239Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,143,827 control chromosomes in the GnomAD database, including 11 homozygotes. There are 893 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., 44 hem., cov: 25)

Exomes 𝑓: 0.0028 ( 8 hom. 849 hem. )

Consequence

CCDC22
NM_014008.5 missense, splice_region

Scores

Splicing: ADA: 0.9938

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.35

Publications

8 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant X-49246731-G-A is Benign according to our data. Variant chrX-49246731-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CCDC22	NM_014008.5 link	c.715G>A	p.Glu239Lys	missense_variant, splice_region_variant	Exon 7 of 17	ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5 link	c.712G>A	p.Glu238Lys	missense_variant, splice_region_variant	Exon 7 of 17		XP_005272656.1
CCDC22	XR_430506.4 link	n.882G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4 link	c.715G>A	p.Glu239Lys	missense_variant, splice_region_variant	Exon 7 of 17	1	NM_014008.5	ENSP00000365401.3

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

217

AN:

112937

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000279

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000355

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.000661

GnomAD2 exomes

AF:

0.00124

AC:

129

AN:

103874

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000558

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000287

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.00277

AC:

2851

AN:

1030839

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

849

AN XY:

325181

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

24574

American (AMR)

AF:

0.000891

AC:

AN:

26933

Ashkenazi Jewish (ASJ)

AF:

0.000254

AC:

AN:

15731

East Asian (EAS)

AF:

0.00

AC:

AN:

28907

South Asian (SAS)

AF:

0.000386

AC:

AN:

44056

European-Finnish (FIN)

AF:

0.000302

AC:

AN:

36427

Middle Eastern (MID)

AF:

0.000316

AC:

AN:

3163

European-Non Finnish (NFE)

AF:

0.00335

AC:

2703

AN:

807977

Other (OTH)

AF:

0.00202

AC:

AN:

43071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00192

AC:

217

AN:

112988

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

35144

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

31194

American (AMR)

AF:

0.000279

AC:

AN:

10754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.000357

AC:

AN:

2805

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00369

AC:

197

AN:

53316

Other (OTH)

AF:

0.000652

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00268

Hom.:

107

Bravo

AF:

0.00168

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.000792

AC:

ESP6500EA

AF:

0.00225

AC:

ExAC

AF:

0.000941

AC:

110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23563313) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 02, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.4

PhyloP100

2.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.48

Sift

Uncertain

0.0090

Sift4G

Benign

0.061

Polyphen

0.98

Vest4

0.38

MVP

0.33

MPC

0.46

ClinPred

0.099

GERP RS

4.1

Varity_R

0.25

gMVP

0.52

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.74

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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