X-49243407-G-A

Position:

• chrX-49243407-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014008.5(CCDC22):​c.659G>A​(p.Arg220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,202,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 84 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 7 hem., cov: 24)
  • Exomes 𝑓: 0.00023 (0 hom. 77 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:3
• Conservation: PhyloP100: -0.100

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020237684).
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC22	NM_014008.5	c.659G>A	p.Arg220Gln	missense_variant	6/17	ENST00000376227.4
CCDC22	XM_005272599.5	c.656G>A	p.Arg219Gln	missense_variant	6/17
CCDC22	XR_430506.4	n.826G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC22	ENST00000376227.4	c.659G>A	p.Arg220Gln	missense_variant	6/17	1	NM_014008.5	P1
CCDC22	ENST00000496651.5	n.750G>A		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 27 AN: 112600 Hom.: 0 Cov.: 24 AF XY: 0.000201 AC XY: 7 AN XY: 34758

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000558

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.000656

GnomAD3 exomes AF: 0.000291 AC: 47 AN: 161441 Hom.: 0 AF XY: 0.000254 AC XY: 13 AN XY: 51217

Gnomad AFR exome AF: 0.0000868

Gnomad AMR exome AF: 0.000778

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000226 AC: 246 AN: 1089659 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 77 AN XY: 356639

Gnomad4 AFR exome AF: 0.000647

Gnomad4 AMR exome AF: 0.000728

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000459

GnomAD4 genome AF: 0.000240 AC: 27 AN: 112653 Hom.: 0 Cov.: 24 AF XY: 0.000201 AC XY: 7 AN XY: 34821

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000557

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000282

Gnomad4 OTH AF: 0.000648

Alfa AF: 0.000253 Hom.: 3

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	The c.659G>A (p.R220Q) alteration is located in exon 6 (coding exon 6) of the CCDC22 gene. This alteration results from a G to A substitution at nucleotide position 659, causing the arginine (R) at amino acid position 220 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2015	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.062
DANN	Benign	0.90
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.023
Sift	Benign	0.42	T
Sift4G	Benign	0.61	T
Polyphen		0.0020	B
Vest4		0.16
MVP		0.36
MPC		0.13
ClinPred		0.0015	T
GERP RS		0.60
Varity_R		0.027
gMVP		0.18

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

Other links and lift over

dbSNP: rs201088755; hg19: chrX-49099873; COSMIC: COSV100879914; COSMIC: COSV100879914;