rs144632022

Positions:

• chrX-49248482-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 95548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49248482-G-A is described in Lovd as [Likely_benign]. Variant chrX-49248482-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 2780 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC22	NM_014008.5	c.1288G>A	p.Ala430Thr	missense_variant	11/17	ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5	c.1285G>A	p.Ala429Thr	missense_variant	11/17		XP_005272656.1
CCDC22	XR_430506.4	n.1451G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC22	ENST00000376227.4	c.1288G>A	p.Ala430Thr	missense_variant	11/17	1	NM_014008.5	ENSP00000365401	P1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 663 AN: 111517 Hom.: 2 Cov.: 23 AF XY: 0.00534 AC XY: 180 AN XY: 33715

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

GnomAD3 exomes AF: 0.00737 AC: 1320 AN: 179019 Hom.: 3 AF XY: 0.00665 AC XY: 431 AN XY: 64833

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 SAS exome AF: 0.00408

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

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00404

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.00807

Gnomad4 OTH exome AF: 0.00797

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

Gnomad4 AFR AF: 0.00117

Gnomad4 AMR AF: 0.00443

Gnomad4 ASJ AF: 0.00833

Gnomad4 EAS AF: 0.000284

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00820

Gnomad4 OTH AF: 0.00591

Alfa AF: 0.00833 Hom.: 336

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 12, 2013

- -

Ritscher-Schinzel syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.55	N
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

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