chrX-49243407-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014008.5(CCDC22):c.659G>A(p.Arg220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,202,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 84 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 7 hem., cov: 24)

Exomes 𝑓: 0.00023 ( 0 hom. 77 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.100

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020237684).

BP6

Variant X-49243407-G-A is Benign according to our data. Variant chrX-49243407-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128627.

BS2

High Hemizygotes in GnomAd4 at 7 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC22	NM_014008.5 link	c.659G>A	p.Arg220Gln	missense_variant	Exon 6 of 17	ENST00000376227.4	NP_054727.1	O60826A0A024QZ03
CCDC22	XM_005272599.5 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 6 of 17		XP_005272656.1
CCDC22	XR_430506.4 link	n.826G>A		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC22	ENST00000376227.4 link	c.659G>A	p.Arg220Gln	missense_variant	Exon 6 of 17	1	NM_014008.5	ENSP00000365401.3	O60826
CCDC22	ENST00000496651.5 link	n.750G>A		non_coding_transcript_exon_variant	Exon 6 of 6	3
CCDC22	ENST00000490300.1 link	n.*61G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000240

AC:

AN:

112600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000558

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000282

Gnomad OTH

AF:

0.000656

GnomAD2 exomes

AF:

0.000291

AC:

AN:

161441

AF XY:

0.000254

show subpopulations

Gnomad AFR exome

AF:

0.0000868

Gnomad AMR exome

AF:

0.000778

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000313

Gnomad OTH exome

AF:

0.000985

GnomAD4 exome

AF:

0.000226

AC:

246

AN:

1089659

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

AN XY:

356639

show subpopulations

African (AFR)

AF:

0.000647

AC:

AN:

26256

American (AMR)

AF:

0.000728

AC:

AN:

34318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19102

East Asian (EAS)

AF:

0.00

AC:

AN:

29853

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39669

Middle Eastern (MID)

AF:

0.00171

AC:

AN:

4087

European-Non Finnish (NFE)

AF:

0.000209

AC:

175

AN:

837991

Other (OTH)

AF:

0.000459

AC:

AN:

45731

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000240

AC:

AN:

112653

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

34821

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

31038

American (AMR)

AF:

0.000557

AC:

AN:

10764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6231

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000282

AC:

AN:

53241

Other (OTH)

AF:

0.000648

AC:

AN:

1543

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000253

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000199

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CCDC22: BP4, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

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

Uncertain:1Benign:1

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.659G>A (p.R220Q) alteration is located in exon 6 (coding exon 6) of the CCDC22 gene. This alteration results from a G to A substitution at nucleotide position 659, causing the arginine (R) at amino acid position 220 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.062

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.17

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.70

M_CAP

Benign

0.012

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.10

PrimateAI

Benign

0.24

PROVEAN

Benign

0.68

REVEL

Benign

0.023

Sift

Benign

0.42

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.16

MVP

0.36

MPC

0.13

ClinPred

0.0015

GERP RS

0.60

Varity_R

0.027

gMVP

0.18

Mutation Taster

=97/3

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over