Variant X-49242907-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_014008.5(CCDC22):c.383G>A(p.Arg128Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000251 in 1,157,410 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 0 hom. 8 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.77

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCDC22	NM_014008.5 linkuse as main transcript	c.383G>A	p.Arg128Gln	missense_variant	4/17	ENST00000376227.4
CCDC22	XM_005272599.5 linkuse as main transcript	c.383G>A	p.Arg128Gln	missense_variant	4/17
CCDC22	XR_430506.4 linkuse as main transcript	n.550G>A		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CCDC22	ENST00000376227.4 linkuse as main transcript	c.383G>A	p.Arg128Gln	missense_variant	4/17	1	NM_014008.5	P1
CCDC22	ENST00000490300.1 linkuse as main transcript	n.526G>A		non_coding_transcript_exon_variant	3/5	3
CCDC22	ENST00000496651.5 linkuse as main transcript	n.474G>A		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111271

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33503

show subpopulations

Gnomad AFR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000813

AC:

AN:

122949

Hom.:

AF XY:

0.0000721

AC XY:

AN XY:

27727

show subpopulations

Gnomad AFR exome

AF:

0.0000941

Gnomad AMR exome

AF:

0.000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000934

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000322

GnomAD4 exome

AF:

0.0000258

AC:

AN:

1046139

Hom.:

Cov.:

AF XY:

0.0000242

AC XY:

AN XY:

331103

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000424

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000346

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000859

Gnomad4 OTH exome

AF:

0.0000911

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111271

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33503

show subpopulations

Gnomad4 AFR

AF:

0.0000656

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000793

ExAC

AF:

0.0000667

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ritscher-Schinzel syndrome 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 07, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.66

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Benign

0.19

Sift

Uncertain

0.011

Sift4G

Uncertain

0.049

Polyphen

0.60

Vest4

0.67

MutPred

0.72

Loss of MoRF binding (P = 0.112);

MVP

0.62

MPC

0.19

ClinPred

0.034

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.30

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over