X-49249509-G-A

Position:

chrX-49249509-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_014008.5(CCDC22):c.1636G>A(p.Asp546Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00518 in 1,203,580 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,906 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., 89 hem., cov: 21)

Exomes 𝑓: 0.0053 ( 15 hom. 1817 hem. )

Consequence

CCDC22
NM_014008.5 missense, splice_region

Scores

Splicing: ADA: 0.9990

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.05

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:

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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. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant X-49249509-G-A is Benign according to our data. Variant chrX-49249509-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49249509-G-A is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 89 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC22	NM_014008.5 linkuse as main transcript	c.1636G>A	p.Asp546Asn	missense_variant, splice_region_variant	15/17	ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5 linkuse as main transcript	c.1633G>A	p.Asp545Asn	missense_variant, splice_region_variant	15/17		XP_005272656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4 linkuse as main transcript	c.1636G>A	p.Asp546Asn	missense_variant, splice_region_variant	15/17	1	NM_014008.5	ENSP00000365401	P1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

376

AN:

108215

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

AN XY:

30857

show subpopulations

Gnomad AFR

AF:

0.000843

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00110

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00206

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00593

Gnomad OTH

AF:

0.000693

GnomAD3 exomes

AF:

0.00350

AC:

641

AN:

183077

Hom.:

AF XY:

0.00363

AC XY:

246

AN XY:

67767

show subpopulations

Gnomad AFR exome

AF:

0.000914

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00178

Gnomad FIN exome

AF:

0.00182

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00534

AC:

5854

AN:

1095319

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

1817

AN XY:

360837

show subpopulations

Gnomad4 AFR exome

AF:

0.000493

Gnomad4 AMR exome

AF:

0.00151

Gnomad4 ASJ exome

AF:

0.00393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.00631

Gnomad4 OTH exome

AF:

0.00503

GnomAD4 genome

AF:

0.00347

AC:

376

AN:

108261

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

AN XY:

30917

show subpopulations

Gnomad4 AFR

AF:

0.000841

Gnomad4 AMR

AF:

0.00110

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00206

Gnomad4 FIN

AF:

0.00218

Gnomad4 NFE

AF:

0.00593

Gnomad4 OTH

AF:

0.000684

Alfa

AF:

0.00472

Hom.:

180

Bravo

AF:

0.00296

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00699

AC:

ExAC

AF:

0.00394

AC:

479

EpiCase

AF:

0.00556

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.48

Sift

Benign

0.094

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.20

MVP

0.65

MPC

0.54

ClinPred

0.014

GERP RS

5.4

Varity_R

0.67

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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