rs199809018

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id is 198556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49246731-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC22	NM_014008.5 link	c.715G>A	p.Glu239Lys	missense_variant, splice_region_variant	Exon 7 of 17	ENST00000376227.4	NP_054727.1	O60826A0A024QZ03
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		O60826

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

217

AN:

112937

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

35083

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

GnomAD3 exomes

AF:

0.00124

AC:

129

AN:

103874

Hom.:

AF XY:

0.00150

AC XY:

AN XY:

22070

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 SAS exome

AF:

0.000137

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

Gnomad4 AFR exome

AF:

0.000163

Gnomad4 AMR exome

AF:

0.000891

Gnomad4 ASJ exome

AF:

0.000254

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000386

Gnomad4 FIN exome

AF:

0.000302

Gnomad4 NFE exome

AF:

0.00335

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00192

AC:

217

AN:

112988

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

35144

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000279

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000357

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00369

Gnomad4 OTH

AF:

0.000652

Alfa

AF:

0.00292

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) -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 19, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: 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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over