Genetic Variant CCDC22:p.Arg384Ser (chrX-49248248-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014008.5(CCDC22):c.1150C>A(p.Arg384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,203,024 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R384C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 5 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.316

Publications

10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13090053).

BS2

High Hemizygotes in GnomAd4 at 9 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014008.5. 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
	CCDC22	NM_014008.5	MANE Select	c.1150C>A	p.Arg384Ser	missense	Exon 10 of 17	NP_054727.1	O60826

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC22	ENST00000376227.4	TSL:1 MANE Select	c.1150C>A	p.Arg384Ser	missense	Exon 10 of 17	ENSP00000365401.3	O60826
CCDC22	ENST00000960401.1		c.1174C>A	p.Arg392Ser	missense	Exon 10 of 17	ENSP00000630460.1
CCDC22	ENST00000904959.1		c.1168C>A	p.Arg390Ser	missense	Exon 10 of 17	ENSP00000575018.1

Frequencies

GnomAD3 genomes

AF:

0.000301

AC:

AN:

109530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000289

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000684

GnomAD2 exomes

AF:

0.0000689

AC:

AN:

174156

AF XY:

0.0000319

show subpopulations

Gnomad AFR exome

AF:

0.000885

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1093494

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361018

show subpopulations

African (AFR)

AF:

0.000948

AC:

AN:

26371

American (AMR)

AF:

0.0000284

AC:

AN:

35155

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30176

South Asian (SAS)

AF:

0.00

AC:

AN:

54010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3901

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841807

Other (OTH)

AF:

0.0000217

AC:

AN:

45999

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000301

AC:

AN:

109530

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

31908

show subpopulations

African (AFR)

AF:

0.000965

AC:

AN:

30055

American (AMR)

AF:

0.000289

AC:

AN:

10385

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3427

South Asian (SAS)

AF:

0.00

AC:

AN:

2538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5751

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52379

Other (OTH)

AF:

0.000684

AC:

AN:

1461

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.000378

ExAC

AF:

0.0000743

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.76

M_CAP

Benign

0.032

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.4

PhyloP100

0.32

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.21

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.026

Polyphen

0.98

Vest4

0.38

MutPred

0.55

Loss of MoRF binding (P = 0.0126)

MVP

0.41

MPC

0.38

ClinPred

0.20

GERP RS

4.1

Varity_R

0.45

gMVP

0.27

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over