rs191605685

Variant names:

• chrX-49243277-C-T
• rs191605685
• NM_014008.5:c.536-7C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014008.5(CCDC22):​c.536-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 1,197,339 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,853 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., 106 hem., cov: 23)
  • Exomes 𝑓: 0.0048 (13 hom. 1747 hem.)
• Consequence: CCDC22 NM_014008.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002202
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.159
• 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-49243277-C-T is Benign according to our data. Variant chrX-49243277-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 106 XL,AR gene

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.536-7C>T		splice_region intron	N/A	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.536-7C>T		splice_region intron	N/A	ENSP00000365401.3	O60826
	CCDC22	ENST00000960401.1		c.560-7C>T		splice_region intron	N/A	ENSP00000630460.1
	CCDC22	ENST00000904959.1		c.554-7C>T		splice_region intron	N/A	ENSP00000575018.1

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 374 AN: 112639 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000904

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00214

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.00363 AC: 584 AN: 160921 AF XY: 0.00413

Gnomad AFR exome AF: 0.000665

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000630

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00248

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00479 AC: 5192 AN: 1084645 Hom.: 13 Cov.: 31 AF XY: 0.00497 AC XY: 1747 AN XY: 351855

African (AFR) AF: 0.000305 AC: 8 AN: 26239

American (AMR) AF: 0.00123 AC: 42 AN: 34139

Ashkenazi Jewish (ASJ) AF: 0.000694 AC: 13 AN: 18725

East Asian (EAS) AF: 0.00 AC: 0 AN: 29934

South Asian (SAS) AF: 0.00526 AC: 274 AN: 52048

European-Finnish (FIN) AF: 0.00258 AC: 103 AN: 39888

Middle Eastern (MID) AF: 0.00859 AC: 35 AN: 4074

European-Non Finnish (NFE) AF: 0.00545 AC: 4543 AN: 834116

Other (OTH) AF: 0.00383 AC: 174 AN: 45482

GnomAD4 genome AF: 0.00333 AC: 375 AN: 112694 Hom.: 0 Cov.: 23 AF XY: 0.00304 AC XY: 106 AN XY: 34862

African (AFR) AF: 0.000902 AC: 28 AN: 31057

American (AMR) AF: 0.00213 AC: 23 AN: 10778

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00404 AC: 11 AN: 2726

European-Finnish (FIN) AF: 0.00255 AC: 16 AN: 6278

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00541 AC: 288 AN: 53200

Other (OTH) AF: 0.00261 AC: 4 AN: 1531

Alfa AF: 0.00465 Hom.: 38

Bravo AF: 0.00260

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Intellectual disability (1)
-	-	1	Ritscher-Schinzel syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.48
DANN	Benign	0.72
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs191605685; hg19: chrX-49099743;