NM_177559.3:c.593A>G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_177559.3(CSNK2A1):c.593A>G(p.Lys198Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_177559.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461822Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727220
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Okur-Chung neurodevelopmental syndrome Pathogenic:13
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3-SUP, PS4, PM2_SUP, PP2 -
The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241, PS2_VS). It has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Okur-Chung neurodevelopmental syndrome (MIM#617062). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten individuals with Okur-Chung neurodevelopmental syndrome (MIM#617062), the majority of whom were due to de novo events (ClinVar, PMID: 29383814, 30655572). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-08 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
PS4;PM1;PM2_supporting;PM6;PP2;PP3 -
The heterozygous de-novo variant c.593A>G (p.Lys198Arg) has been identified in a 4months old female proband with seizures, bilateral cherry red spots, multiple episodes of apnea and cyanosis, generalized edema, dyskinetic movements of both upper limbs. This variant is identified in exon 8 which is a hotspot exon for CSNK2A1 gene (PM1_supporting). 26 pathogenic mis-sense variants have been identified in this gene (PP2_supporting). The population frequency in gnomAD (aggregated) is 0.0004% (PM2_moderate). This variant has been identified previously PMID 27048600 (PP5_very strong). -
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The p.Lys198Arg variant in the CSNK2A1 gene has been previously reported de novo in 8 unrelated individuals with Okur-Chung neurodevelopmental syndrome (Okur et al., 2016; Owen et al., 2017; Chiu et al., 2018; Akahira-Azuma et al., 2018; Nakashima et al., 2019). This variant has also been identified in 1/251361 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CSNK2A1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys198Arg variant as pathogenic for autosomal dominant Okur-Chung neurodevelopmental syndrome based on the information above. [ACMG evidence codes used: PS2; PS4; PP2] -
PM2_Supporting+PP2+PS4_Moderate+PM6_Strong+PM1 -
not provided Pathogenic:5
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to be de novo in individuals affected with Okur-Chung neurodevelopmental syndrome (PMID: 27048600, 29619237, 29383814, 29240241). ClinVar contains an entry for this variant (Variation ID: 224790). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 198 of the CSNK2A1 protein (p.Lys198Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -
Published functional studies demonstrate a damaging effect (altered binding specificity) (Caefer et al., 2022; Werner et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30655572, 32746809, 27048600, 29619237, 25363768, 28135719, 29383814, 28191890, 30109123, 29240241, 31060130, 28714951, 32651551, 34011629, 33726816, 31785789, 33994545, 35445078, 33944995, 35517865) -
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Neurodevelopmental delay Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.593A>G (p.K198R) alteration is located in exon 9 (coding exon 7) of the CSNK2A1 gene. This alteration results from an A to G substitution at nucleotide position 593, causing the lysine (K) at amino acid position 198 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251364) total alleles studied. The p.K198R alteration is the most common alteration in Okur-Chung syndrome and has been reported as de novo in multiple patients (Iossifov, 2014; Okur, 2016; Akahira-Azuma, 2018; Owen, 2018; Chiu, 2018). Based on the available evidence, this alteration is classified as pathogenic. -
See cases Pathogenic:1
PVS1_strong;PM2_supporting;PM6_moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at