X-49242106-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_014008.5(CCDC22):c.319C>T(p.Arg107Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,097,673 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.21

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC22	NM_014008.5	c.319C>T	p.Arg107Cys	missense_variant	3/17	ENST00000376227.4
CCDC22	XM_005272599.5	c.319C>T	p.Arg107Cys	missense_variant	3/17
CCDC22	XR_430506.4	n.486C>T		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC22	ENST00000376227.4	c.319C>T	p.Arg107Cys	missense_variant	3/17	1	NM_014008.5	P1
CCDC22	ENST00000490300.1	n.462C>T		non_coding_transcript_exon_variant	2/5	3
CCDC22	ENST00000496651.5	n.410C>T		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097673 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363047

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.319C>T (p.R107C) alteration is located in exon 3 (coding exon 3) of the CCDC22 gene. This alteration results from a C to T substitution at nucleotide position 319, causing the arginine (R) at amino acid position 107 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ritscher-Schinzel syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 11, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss-of-function is a likely mechanism of disease (PMIDs: 24916641, 23563313, 21826058). (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 3). (N) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (DUF812 domain; NCBI, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.45
MVP		0.59
MPC		2.0
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.60

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: rs2065966338; hg19: chrX-49098572;