rs144685788

Positions:

• chrX-49247746-C-G
• chrX-49247746-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014008.5(CCDC22):​c.1070C>G​(p.Thr357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,209,533 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 104 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., 54 hem., cov: 24)
  • Exomes 𝑓: 0.00018 (0 hom. 50 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.574

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004600495).
• BP6: Variant X-49247746-C-G is Benign according to our data. Variant chrX-49247746-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 210614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC22	NM_014008.5	c.1070C>G	p.Thr357Ser	missense_variant	9/17	ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5	c.1067C>G	p.Thr356Ser	missense_variant	9/17		XP_005272656.1
CCDC22	XR_430506.4	n.1237C>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4	c.1070C>G	p.Thr357Ser	missense_variant	9/17	1	NM_014008.5	ENSP00000365401	P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 189 AN: 112149 Hom.: 0 Cov.: 24 AF XY: 0.00157 AC XY: 54 AN XY: 34329

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000559

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000564 AC: 101 AN: 179143 Hom.: 0 AF XY: 0.000292 AC XY: 19 AN XY: 65069

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.000294

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: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 203 AN: 1097328 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 50 AN XY: 362824

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.000313

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: 0.00000594

Gnomad4 OTH exome AF: 0.000499

GnomAD4 genome AF: 0.00168 AC: 189 AN: 112205 Hom.: 0 Cov.: 24 AF XY: 0.00157 AC XY: 54 AN XY: 34395

Gnomad4 AFR AF: 0.00576

Gnomad4 AMR AF: 0.000559

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000565

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000277 Hom.: 4

Bravo AF: 0.00192

ESP6500AA AF: 0.00757 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000594 AC: 72

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.14
DANN	Benign	0.59
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.011
Sift	Benign	0.62	T
Sift4G	Benign	0.72	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.35		Gain of phosphorylation at T357 (P = 0.0414);
MVP		0.24
MPC		0.10
ClinPred		0.0015	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.077

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: rs144685788; hg19: chrX-49104207;