Genetic Variant NM_014008.5:c.659G>C (chrX-49243407-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014008.5(CCDC22):c.659G>C(p.Arg220Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,659 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.100

Publications

0 publications found

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 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

CCDC22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40949935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC22	NM_014008.5 link	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 17	ENST00000376227.4	NP_054727.1	O60826A0A024QZ03
CCDC22	XM_005272599.5 link	c.656G>C	p.Arg219Pro	missense_variant	Exon 6 of 17		XP_005272656.1
CCDC22	XR_430506.4 link	n.826G>C		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC22	ENST00000376227.4 link	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 17	1	NM_014008.5	ENSP00000365401.3	O60826
CCDC22	ENST00000496651.5 link	n.750G>C		non_coding_transcript_exon_variant	Exon 6 of 6	3
CCDC22	ENST00000490300.1 link	n.*61G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1089659

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

356639

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

34318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19102

East Asian (EAS)

AF:

0.00

AC:

AN:

29853

South Asian (SAS)

AF:

0.00

AC:

AN:

52653

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39669

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4087

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

837990

Other (OTH)

AF:

0.00

AC:

AN:

45731

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.29

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.25

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.73

M_CAP

Benign

0.021

MetaRNN

Benign

0.41

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.10

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.67

REVEL

Benign

0.12

Sift

Benign

0.18

Sift4G

Benign

0.28

Polyphen

0.52

Vest4

0.50

MutPred

0.63

Gain of loop (P = 0.1081);

MVP

0.33

MPC

0.33

ClinPred

0.29

GERP RS

0.60

Varity_R

0.16

gMVP

0.42

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over