X-49246731-G-A

Variant names:

• chrX-49246731-G-A
• rs199809018
• NM_014008.5:c.715G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

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
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId is 198556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	NM_014008.5	MANE Select	c.715G>A	p.Glu239Lys	missense splice_region	Exon 7 of 17	NP_054727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	ENST00000376227.4	TSL:1 MANE Select	c.715G>A	p.Glu239Lys	missense splice_region	Exon 7 of 17	ENSP00000365401.3

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 217 AN: 112937 Hom.: 3 Cov.: 25

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

GnomAD2 exomes AF: 0.00124 AC: 129 AN: 103874 AF XY: 0.00150

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 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.: 8 Cov.: 28 AF XY: 0.00261 AC XY: 849 AN XY: 325181

African (AFR) AF: 0.000163 AC: 4 AN: 24574

American (AMR) AF: 0.000891 AC: 24 AN: 26933

Ashkenazi Jewish (ASJ) AF: 0.000254 AC: 4 AN: 15731

East Asian (EAS) AF: 0.00 AC: 0 AN: 28907

South Asian (SAS) AF: 0.000386 AC: 17 AN: 44056

European-Finnish (FIN) AF: 0.000302 AC: 11 AN: 36427

Middle Eastern (MID) AF: 0.000316 AC: 1 AN: 3163

European-Non Finnish (NFE) AF: 0.00335 AC: 2703 AN: 807977

Other (OTH) AF: 0.00202 AC: 87 AN: 43071

GnomAD4 genome AF: 0.00192 AC: 217 AN: 112988 Hom.: 3 Cov.: 25 AF XY: 0.00125 AC XY: 44 AN XY: 35144

African (AFR) AF: 0.000481 AC: 15 AN: 31194

American (AMR) AF: 0.000279 AC: 3 AN: 10754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.000357 AC: 1 AN: 2805

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00369 AC: 197 AN: 53316

Other (OTH) AF: 0.000652 AC: 1 AN: 1533

Alfa AF: 0.00268 Hom.: 107

Bravo AF: 0.00168

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.000792 AC: 3

ESP6500EA AF: 0.00225 AC: 15

ExAC AF: 0.000941 AC: 110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.061	T
Polyphen		0.98	D
Vest4		0.38
MVP		0.33
MPC		0.46
ClinPred		0.099	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.52
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs199809018; hg19: chrX-49103192; COSMIC: COSV66050908; COSMIC: COSV66050908;