X-49248248-C-T

Position:

chrX-49248248-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000376227.4(CCDC22):c.1150C>T(p.Arg384Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,203,066 control chromosomes in the GnomAD database, including 4 homozygotes. There are 1,646 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 0.0036 ( 0 hom., 99 hem., cov: 22)

Exomes 𝑓: 0.0044 ( 4 hom. 1547 hem. )

Consequence

CCDC22
ENST00000376227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.316

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008935094).

BP6

Variant X-49248248-C-T is Benign according to our data. Variant chrX-49248248-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210615.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}. Variant chrX-49248248-C-T is described in Lovd as [Benign]. Variant chrX-49248248-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 99 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CCDC22	NM_014008.5 linkuse as main transcript	c.1150C>T	p.Arg384Cys	missense_variant	10/17	ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5 linkuse as main transcript	c.1147C>T	p.Arg383Cys	missense_variant	10/17		XP_005272656.1
CCDC22	XR_430506.4 linkuse as main transcript	n.1313C>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4 linkuse as main transcript	c.1150C>T	p.Arg384Cys	missense_variant	10/17	1	NM_014008.5	ENSP00000365401	P1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

398

AN:

109530

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

100

AN XY:

31908

show subpopulations

Gnomad AFR

AF:

0.00103

Gnomad AMI

AF:

0.0120

Gnomad AMR

AF:

0.00587

Gnomad ASJ

AF:

0.000381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00844

Gnomad NFE

AF:

0.00542

Gnomad OTH

AF:

0.00342

GnomAD3 exomes

AF:

0.00296

AC:

516

AN:

174156

Hom.:

AF XY:

0.00266

AC XY:

167

AN XY:

62736

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00323

Gnomad ASJ exome

AF:

0.000824

Gnomad EAS exome

AF:

0.0000735

Gnomad SAS exome

AF:

0.000956

Gnomad FIN exome

AF:

0.00124

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00390

GnomAD4 exome

AF:

0.00437

AC:

4782

AN:

1093489

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

1547

AN XY:

361015

show subpopulations

Gnomad4 AFR exome

AF:

0.000455

Gnomad4 AMR exome

AF:

0.00339

Gnomad4 ASJ exome

AF:

0.000981

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.000778

Gnomad4 FIN exome

AF:

0.00139

Gnomad4 NFE exome

AF:

0.00515

Gnomad4 OTH exome

AF:

0.00413

GnomAD4 genome

AF:

0.00361

AC:

396

AN:

109577

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

AN XY:

31965

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00587

Gnomad4 ASJ

AF:

0.000381

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00538

Gnomad4 OTH

AF:

0.00338

Alfa

AF:

0.00449

Hom.:

Bravo

AF:

0.00354

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00242

AC:

ESP6500AA

AF:

0.00157

AC:

ESP6500EA

AF:

0.00461

AC:

ExAC

AF:

0.00307

AC:

372

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2014	- -

not provided

Benign:2

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	Nov 11, 2016	- -

CCDC22-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.12

MVP

0.38

MPC

0.60

ClinPred

0.055

GERP RS

4.1

Varity_R

0.42

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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