chr20-10412638-A-ACAGG
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000347364.7(MKKS):c.873_876dupCCTG(p.Cys293ProfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L292L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
MKKS
ENST00000347364.7 frameshift
ENST00000347364.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.152
Publications
3 publications found
Genes affected
MKKS (HGNC:7108): (MKKS centrosomal shuttling protein) This gene encodes a protein which shares sequence similarity with other members of the type II chaperonin family. The encoded protein is a centrosome-shuttling protein and plays an important role in cytokinesis. This protein also interacts with other type II chaperonin members to form a complex known as the BBSome, which involves ciliary membrane biogenesis. This protein is encoded by a downstream open reading frame (dORF). Several upstream open reading frames (uORFs) have been identified, which repress the translation of the dORF, and two of which can encode small mitochondrial membrane proteins. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 6, also known as McKusick-Kaufman syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2023]
MKKS Gene-Disease associations (from GenCC):
- McKusick-Kaufman syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
- Bardet-Biedl syndrome 6Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- Bardet-Biedl syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-10412638-A-ACAGG is Pathogenic according to our data. Variant chr20-10412638-A-ACAGG is described in ClinVar as Pathogenic. ClinVar VariationId is 21672.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000347364.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MKKS | NM_170784.3 | MANE Select | c.873_876dupCCTG | p.Cys293ProfsTer35 | frameshift | Exon 3 of 6 | NP_740754.1 | ||
| MKKS | NM_018848.3 | c.873_876dupCCTG | p.Cys293ProfsTer35 | frameshift | Exon 3 of 6 | NP_061336.1 | |||
| MKKS | NR_072977.2 | n.347-3839_347-3836dupCCTG | intron | N/A |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MKKS | ENST00000347364.7 | TSL:1 MANE Select | c.873_876dupCCTG | p.Cys293ProfsTer35 | frameshift | Exon 3 of 6 | ENSP00000246062.4 | ||
| MKKS | ENST00000399054.6 | TSL:1 | c.873_876dupCCTG | p.Cys293ProfsTer35 | frameshift | Exon 3 of 6 | ENSP00000382008.2 | ||
| MKKS | ENST00000651692.1 | c.873_876dupCCTG | p.Cys293ProfsTer35 | frameshift | Exon 4 of 7 | ENSP00000498849.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727232 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1461860
Hom.:
Cov.:
33
AF XY:
AC XY:
4
AN XY:
727232
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1112000
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
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0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Bardet-Biedl syndrome (1)
1
-
-
MKKS-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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