rs770908659
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_170784.3(MKKS):c.958_959delCT(p.Leu320AspfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000031 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
MKKS
NM_170784.3 frameshift
NM_170784.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.65
Publications
1 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
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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 20-10412555-CAG-C is Pathogenic according to our data. Variant chr20-10412555-CAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_170784.3. 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.958_959delCT | p.Leu320AspfsTer6 | frameshift | Exon 3 of 6 | NP_740754.1 | ||
| MKKS | NM_018848.3 | c.958_959delCT | p.Leu320AspfsTer6 | frameshift | Exon 3 of 6 | NP_061336.1 | |||
| MKKS | NR_072977.2 | n.347-3754_347-3753delCT | intron | N/A |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MKKS | ENST00000347364.7 | TSL:1 MANE Select | c.958_959delCT | p.Leu320AspfsTer6 | frameshift | Exon 3 of 6 | ENSP00000246062.4 | ||
| MKKS | ENST00000399054.6 | TSL:1 | c.958_959delCT | p.Leu320AspfsTer6 | frameshift | Exon 3 of 6 | ENSP00000382008.2 | ||
| MKKS | ENST00000651692.1 | c.958_959delCT | p.Leu320AspfsTer6 | frameshift | Exon 4 of 7 | ENSP00000498849.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.00000797 AC: 2AN: 251074 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251074
AF XY:
Gnomad AFR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461682Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727148 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1461682
Hom.:
AF XY:
AC XY:
3
AN XY:
727148
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
1
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:
53264
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1111974
Other (OTH)
AF:
AC:
1
AN:
60388
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000286219), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.388
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74354
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41452
American (AMR)
AF:
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5202
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68028
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
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EpiControl
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ClinVar
ClinVar submissions as Germline
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome (1)
1
-
-
Polycystic kidney disease;C3714581:Multicystic kidney dysplasia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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