rs140735182

Positions:

• chrX-49247548-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014008.5(CCDC22):​c.962G>A​(p.Arg321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,196,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 158 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., 16 hem., cov: 24)
  • Exomes 𝑓: 0.00037 (0 hom. 142 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.05

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003258437).
• BP6: Variant X-49247548-G-A is Benign according to our data. Variant chrX-49247548-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198853.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chrX-49247548-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC22	NM_014008.5	c.962G>A	p.Arg321Gln	missense_variant	8/17	ENST00000376227.4
CCDC22	XM_005272599.5	c.959G>A	p.Arg320Gln	missense_variant	8/17
CCDC22	XR_430506.4	n.1129G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC22	ENST00000376227.4	c.962G>A	p.Arg321Gln	missense_variant	8/17	1	NM_014008.5	P1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 60 AN: 112517 Hom.: 0 Cov.: 24 AF XY: 0.000461 AC XY: 16 AN XY: 34675

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0143

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000783 AC: 120 AN: 153298 Hom.: 0 AF XY: 0.000872 AC XY: 42 AN XY: 48186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000398

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000623

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.000374 AC: 406 AN: 1084125 Hom.: 0 Cov.: 31 AF XY: 0.000401 AC XY: 142 AN XY: 353739

Gnomad4 AFR exome AF: 0.0000384

Gnomad4 AMR exome AF: 0.000119

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000327

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000533 AC: 60 AN: 112572 Hom.: 0 Cov.: 24 AF XY: 0.000461 AC XY: 16 AN XY: 34740

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0143

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000282

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000908 Hom.: 22

Bravo AF: 0.000518

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.000602 AC: 72

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.19
DANN	Benign	0.80
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.048
Sift	Benign	0.59	T
Sift4G	Benign	0.57	T
Polyphen		0.0020	B
Vest4		0.054
MVP		0.27
MPC		0.13
ClinPred		0.0037	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140735182; hg19: chrX-49104009;