rs140735182

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.962G>A(p.Arg321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,196,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 158 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).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 16 hem., cov: 24)

Exomes 𝑓: 0.00037 ( 0 hom. 142 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.05

Publications

3 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=0.003258437).

BP6

Variant X-49247548-G-A is Benign according to our data. Variant chrX-49247548-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198853.

BS2

High Hemizygotes in GnomAd4 at 16 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC22	NM_014008.5 link	c.962G>A	p.Arg321Gln	missense_variant	Exon 8 of 17	ENST00000376227.4	NP_054727.1	O60826A0A024QZ03
CCDC22	XM_005272599.5 link	c.959G>A	p.Arg320Gln	missense_variant	Exon 8 of 17		XP_005272656.1
CCDC22	XR_430506.4 link	n.1129G>A		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4 link	c.962G>A	p.Arg321Gln	missense_variant	Exon 8 of 17	1	NM_014008.5	ENSP00000365401.3		O60826

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

112517

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0143

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00110

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000282

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000783

AC:

120

AN:

153298

AF XY:

0.000872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000398

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.000374

AC:

406

AN:

1084125

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

142

AN XY:

353739

show subpopulations

African (AFR)

AF:

0.0000384

AC:

AN:

26057

American (AMR)

AF:

0.000119

AC:

AN:

33748

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

230

AN:

19111

East Asian (EAS)

AF:

0.00

AC:

AN:

29475

South Asian (SAS)

AF:

0.000327

AC:

AN:

51921

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38920

Middle Eastern (MID)

AF:

0.00323

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

835303

Other (OTH)

AF:

0.00114

AC:

AN:

45564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000533

AC:

AN:

112572

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

AN XY:

34740

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

31049

American (AMR)

AF:

0.00

AC:

AN:

10761

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00110

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6205

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000282

AC:

AN:

53181

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000828

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.000602

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Mar 12, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.19

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.62

M_CAP

Benign

0.066

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

0.74

REVEL

Benign

0.048

Sift

Benign

0.59

Sift4G

Benign

0.57

Polyphen

0.0020

Vest4

0.054

MVP

0.27

MPC

0.13

ClinPred

0.0037

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.094

Mutation Taster

=99/1

polymorphism (auto)

(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

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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