rs587780297

Variant names:

• chrX-49247558-G-C
• rs587780297
• NM_014008.5:c.972G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-49247558-G-C
• chrX-49247558-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM2 PP3_Strong BP6_Moderate

The NM_014008.5(CCDC22):​c.972G>C​(p.Gln324His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 112,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: CCDC22 NM_014008.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant X-49247558-G-C is Benign according to our data. Variant chrX-49247558-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 128628.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	NM_014008.5	MANE Select	c.972G>C	p.Gln324His	missense splice_region	Exon 8 of 17	NP_054727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	ENST00000376227.4	TSL:1 MANE Select	c.972G>C	p.Gln324His	missense splice_region	Exon 8 of 17	ENSP00000365401.3

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112648 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112648 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34796

African (AFR) AF: 0.00 AC: 0 AN: 31003

American (AMR) AF: 0.00 AC: 0 AN: 10770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6235

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.39		Loss of loop (P = 0.1258)
MVP		0.57
MPC		0.47
ClinPred		0.92	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.25
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780297; hg19: chrX-49104019;