chrX-49248482-G-A

Variant names:

• chrX-49248482-G-A
• rs144632022
• NM_014008.5:c.1288G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014008.5(CCDC22):​c.1288G>A​(p.Ala430Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00765 in 1,207,914 control chromosomes in the GnomAD database, including 24 homozygotes. There are 2,961 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (2 hom., 181 hem., cov: 23)
  • Exomes 𝑓: 0.0078 (22 hom. 2780 hem.)
• Consequence: CCDC22 NM_014008.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.63
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008079827).
• BP6: Variant X-49248482-G-A is Benign according to our data. Variant chrX-49248482-G-A is described in ClinVar as Benign. ClinVar VariationId is 95548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00782 (8578/1096345) while in subpopulation MID AF = 0.0247 (102/4123). AF 95% confidence interval is 0.0209. There are 22 homozygotes in GnomAdExome4. There are 2780 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC22	NM_014008.5	MANE Select	c.1288G>A	p.Ala430Thr	missense	Exon 11 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.1288G>A	p.Ala430Thr	missense	Exon 11 of 17	ENSP00000365401.3

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 663 AN: 111517 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00444

Gnomad ASJ AF: 0.00833

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00818

Gnomad OTH AF: 0.00598

GnomAD2 exomes AF: 0.00737 AC: 1320 AN: 179019 AF XY: 0.00665

Gnomad AFR exome AF: 0.000469

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00793

GnomAD4 exome AF: 0.00782 AC: 8578 AN: 1096345 Hom.: 22 Cov.: 34 AF XY: 0.00768 AC XY: 2780 AN XY: 362065

African (AFR) AF: 0.00106 AC: 28 AN: 26379

American (AMR) AF: 0.00358 AC: 126 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 203 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00404 AC: 218 AN: 53929

European-Finnish (FIN) AF: 0.0186 AC: 741 AN: 39911

Middle Eastern (MID) AF: 0.0247 AC: 102 AN: 4123

European-Non Finnish (NFE) AF: 0.00807 AC: 6793 AN: 841292

Other (OTH) AF: 0.00797 AC: 367 AN: 46023

GnomAD4 genome AF: 0.00595 AC: 664 AN: 111569 Hom.: 2 Cov.: 23 AF XY: 0.00536 AC XY: 181 AN XY: 33777

African (AFR) AF: 0.00117 AC: 36 AN: 30759

American (AMR) AF: 0.00443 AC: 47 AN: 10609

Ashkenazi Jewish (ASJ) AF: 0.00833 AC: 22 AN: 2642

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3527

South Asian (SAS) AF: 0.00189 AC: 5 AN: 2640

European-Finnish (FIN) AF: 0.0179 AC: 108 AN: 6038

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

European-Non Finnish (NFE) AF: 0.00820 AC: 434 AN: 52928

Other (OTH) AF: 0.00591 AC: 9 AN: 1523

Alfa AF: 0.00784 Hom.: 338

Bravo AF: 0.00491

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00588 AC: 17

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00803 AC: 54

ExAC AF: 0.00803 AC: 974

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Aug 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ritscher-Schinzel syndrome 2 Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.18
Sift	Benign	0.15	T
Sift4G	Benign	0.54	T
Polyphen		0.99	D
Vest4		0.10
MVP		0.70
MPC		0.44
ClinPred		0.017	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.042
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144632022; hg19: chrX-49104943; COSMIC: COSV99058596; COSMIC: COSV99058596;