chrX-49235685-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_014008.5(CCDC22):​c.49A>C​(p.Thr17Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. 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. T17A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

CCDC22
NM_014008.5 missense, splice_region

Scores

2
10
5
Splicing: ADA: 0.9998
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-49235685-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 218105.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CCDC22NM_014008.5 linkuse as main transcriptc.49A>C p.Thr17Pro missense_variant, splice_region_variant 1/17 ENST00000376227.4
CCDC22XM_005272599.5 linkuse as main transcriptc.49A>C p.Thr17Pro missense_variant, splice_region_variant 1/17
CCDC22XR_430506.4 linkuse as main transcriptn.216A>C splice_region_variant, non_coding_transcript_exon_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CCDC22ENST00000376227.4 linkuse as main transcriptc.49A>C p.Thr17Pro missense_variant, splice_region_variant 1/171 NM_014008.5 P1
CCDC22ENST00000496651.5 linkuse as main transcriptn.190A>C splice_region_variant, non_coding_transcript_exon_variant 1/63

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

ClinVar

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

Submissions by phenotype

Ritscher-Schinzel syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterresearchDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and DevelopmentJan 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Benign
-0.61
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.0
D
REVEL
Uncertain
0.31
Sift
Benign
0.099
T
Sift4G
Uncertain
0.044
D
Polyphen
1.0
D
Vest4
0.45
MutPred
0.72
Gain of disorder (P = 0.0544);
MVP
0.87
MPC
4.3
ClinPred
0.97
D
GERP RS
3.7
Varity_R
0.69
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.050
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-49092145; API