chrX-49237162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014008.5(CCDC22):​c.127C>T​(p.Arg43Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. R43P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CCDC22
NM_014008.5 missense

Scores

6
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.07
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CCDC22NM_014008.5 linkuse as main transcriptc.127C>T p.Arg43Cys missense_variant 2/17 ENST00000376227.4
CCDC22XM_005272599.5 linkuse as main transcriptc.127C>T p.Arg43Cys missense_variant 2/17
CCDC22XR_430506.4 linkuse as main transcriptn.294C>T non_coding_transcript_exon_variant 2/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CCDC22ENST00000376227.4 linkuse as main transcriptc.127C>T p.Arg43Cys missense_variant 2/171 NM_014008.5 P1
CCDC22ENST00000490300.1 linkuse as main transcriptn.270C>T non_coding_transcript_exon_variant 1/53
CCDC22ENST00000496651.5 linkuse as main transcriptn.268C>T non_coding_transcript_exon_variant 2/63

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097458
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
1
AN XY:
362836
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2023Variant summary: CCDC22 c.127C>T (p.Arg43Cys) results in a non-conservative amino acid change located in the CCDC22, N-terminal domain (IPR048349) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182820 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.127C>T in individuals affected with Ritscher-Schinzel Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.62
D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.2
D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.012
D
Polyphen
1.0
D
Vest4
0.54
MutPred
0.77
Loss of MoRF binding (P = 0.083);
MVP
0.73
MPC
2.1
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.65
gMVP
0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49093629; API