chrX-49235638-T-C

Variant names:

• chrX-49235638-T-C
• NM_014008.5:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_014008.5(CCDC22):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000936 in 1,067,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: CCDC22 NM_014008.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.38
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Ritscher-Schinzel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000295652 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 61 codons. Genomic position: 49237216. Lost 0.096 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	NM_014008.5	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 17	NP_054727.1	O60826

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	ENST00000376227.4	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 17	ENSP00000365401.3	O60826
	CCDC22	ENST00000960401.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 17	ENSP00000630460.1
	CCDC22	ENST00000904959.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 17	ENSP00000575018.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.36e-7 AC: 1 AN: 1067814 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 348074

African (AFR) AF: 0.00 AC: 0 AN: 25507

American (AMR) AF: 0.00 AC: 0 AN: 30820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18775

East Asian (EAS) AF: 0.00 AC: 0 AN: 28267

South Asian (SAS) AF: 0.00 AC: 0 AN: 50615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826852

Other (OTH) AF: 0.00 AC: 0 AN: 44846

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CCDC22-related disorder (1)
-	1	-	Ritscher-Schinzel syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.037	T
PhyloP100		3.4
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.72		Gain of catalytic residue at M1 (P = 0.0357)
MVP		0.84
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.22	Neutral
Varity_R		0.94
gMVP		0.98
Mutation Taster		=16/184	disease causing

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

Other links and lift over

hg19: chrX-49092098;