chrX-49246917-T-C

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.901T>C(p.Phe301Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000426 in 1,188,767 control chromosomes in the GnomAD database, including 1 homozygotes. There are 165 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., 18 hem., cov: 24)

Exomes 𝑓: 0.00042 ( 1 hom. 147 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.81

Publications

2 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072934926).

BP6

Variant X-49246917-T-C is Benign according to our data. Variant chrX-49246917-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434617.

BS2

High Hemizygotes in GnomAd4 at 18 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.901T>C	p.Phe301Leu	missense	Exon 7 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.901T>C	p.Phe301Leu	missense	Exon 7 of 17	ENSP00000365401.3	O60826
CCDC22	ENST00000960401.1		c.925T>C	p.Phe309Leu	missense	Exon 7 of 17	ENSP00000630460.1
CCDC22	ENST00000904959.1		c.919T>C	p.Phe307Leu	missense	Exon 7 of 17	ENSP00000575018.1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

112964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000927

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00105

AC:

152

AN:

145018

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000414

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000422

AC:

454

AN:

1075803

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

147

AN XY:

347353

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25877

American (AMR)

AF:

0.0000303

AC:

AN:

33052

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

355

AN:

18972

East Asian (EAS)

AF:

0.00

AC:

AN:

29111

South Asian (SAS)

AF:

0.00

AC:

AN:

51333

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38333

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.0000663

AC:

AN:

829687

Other (OTH)

AF:

0.000948

AC:

AN:

45335

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000460

AC:

AN:

112964

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

AN XY:

35130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31102

American (AMR)

AF:

0.0000927

AC:

AN:

10783

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6325

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53287

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00123

Hom.:

Bravo

AF:

0.000601

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000521

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

M_CAP

Benign

0.040

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.7

PhyloP100

3.8

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.30

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.049

Polyphen

0.99

Vest4

0.44

MutPred

0.75

Gain of ubiquitination at K298 (P = 0.0913)

MVP

0.84

MPC

0.57

ClinPred

0.17

GERP RS

5.0

Varity_R

0.70

gMVP

0.41

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over