X-49247746-C-T

Variant names:

• chrX-49247746-C-T
• rs144685788
• NM_014008.5:c.1070C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014008.5(CCDC22):​c.1070C>T​(p.Thr357Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,327 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T357S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.574
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08209473).

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.1070C>T	p.Thr357Ile	missense	Exon 9 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.1070C>T	p.Thr357Ile	missense	Exon 9 of 17	ENSP00000365401.3	O60826
	CCDC22	ENST00000960401.1		c.1094C>T	p.Thr365Ile	missense	Exon 9 of 17	ENSP00000630460.1
	CCDC22	ENST00000904959.1		c.1088C>T	p.Thr363Ile	missense	Exon 9 of 17	ENSP00000575018.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000558 AC: 1 AN: 179143 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097327 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362823

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.0000284 AC: 1 AN: 35153

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 53944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40295

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841773

Other (OTH) AF: 0.00 AC: 0 AN: 46064

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.4
DANN	Benign	0.93
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.57
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.0090
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.21	B
Vest4		0.21
MutPred		0.50		Loss of ubiquitination at K356 (P = 0.0353)
MVP		0.28
MPC		0.12
ClinPred		0.075	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.14
Mutation Taster		=97/3	polymorphism

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

dbSNP: rs144685788; hg19: chrX-49104207;