rs74315398

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_170784.3(MKKS):c.830T>C(p.Leu277Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:1

Conservation

PhyloP100: 8.55

Publications

7 publications found

Variant links:

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 syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Bardet-Biedl syndrome 6
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MKKS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 20-10412685-A-G is Pathogenic according to our data. Variant chr20-10412685-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5314.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MKKS	NM_170784.3 link	c.830T>C	p.Leu277Pro	missense_variant	Exon 3 of 6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3 link	c.830T>C	p.Leu277Pro	missense_variant	Exon 3 of 6		NP_061336.1
MKKS	NR_072977.2 link	n.347-3882T>C		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MKKS	ENST00000347364.7 link	c.830T>C	p.Leu277Pro	missense_variant	Exon 3 of 6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6 link	c.830T>C	p.Leu277Pro	missense_variant	Exon 3 of 6	1		ENSP00000382008.2
MKKS	ENST00000651692.1 link	c.830T>C	p.Leu277Pro	missense_variant	Exon 4 of 7			ENSP00000498849.1
MKKS	ENST00000652676.1 link	n.474T>C		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251158

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000160

AC:

178

AN:

1112006

Other (OTH)

AF:

0.0000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 09, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 20498079, 20080638); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 30586318, 20498079, 20080638, 11673413, 26900326, 15637713, 31964843, 37217489, 37734845, 22446187, 10973251, 21157496)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bardet-Biedl syndrome 6

Pathogenic:2

Feb 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 27, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

McKusick-Kaufman syndrome;C1858054:Bardet-Biedl syndrome 6

Pathogenic:1

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MKKS-related disorder

Pathogenic:1

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MKKS c.830T>C variant is predicted to result in the amino acid substitution p.Leu277Pro. This variant has been reported in the compound heterozygous state in at least one individual affected with Bardet-Biedl syndrome, and segregated with disease in the family (Katsanis et al. 2000. PubMed ID: 10973251; Moore et al. 2005. PubMed ID: 15637713). Functional studies revealed that this variant causes disruption of the MKKS-BBS12 interaction and could not rescue the morphant phenotype in zebrafish (Seo et al. 2010. PubMed ID: 20080638; Zaghloul et al. 2010. PubMed ID: 20498079, Supplementary Table 5; Hulleman et al. 2016. PubMed ID: 26900326). At PreventionGenetics, we identified this variant in the heterozygous state, along with a second heterozygous pathogenic variant, in an affected patient (internal data). Based on these observations, this variant is classified as pathogenic.

Inborn genetic diseases

Pathogenic:1

Apr 17, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.830T>C (p.L277P) alteration is located in exon 3 (coding exon 1) of the MKKS gene. This alteration results from a T to C substitution at nucleotide position 830, causing the leucine (L) at amino acid position 277 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (17/282570) total alleles studied. This variant has been identified in the homozygous state and/or in conjunction with other MKKS variant(s) in individual(s) with features consistent with MKKS-related ciliopathy; in at least one instance, the variants were identified in trans (Schlottmann, 2023; Kousi, 2020; Groopman, 2019; Pereiro, 2011; Katsanis, 2000; Ambry internal data). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Pathogenic:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 277 of the MKKS protein (p.Leu277Pro). This variant is present in population databases (rs74315398, gnomAD 0.009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10973251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5314). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MKKS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MKKS function (PMID: 20498079, 22446187). For these reasons, this variant has been classified as Pathogenic.

McKusick-Kaufman syndrome

Pathogenic:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Bardet-Biedl syndrome

Pathogenic:1

Apr 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MKKS c.830T>C (p.Leu277Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome (6.4e-05 vs 0.00076), allowing no conclusion about variant significance. c.830T>C has been reported in the literature in both compound heterozygous and homozygous individuals affected with Bardet-Biedl Syndrome and has been reported to segregate with disease in related individuals (e.g., Katsanis_2000, Pereiro_2011, Groopman_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant behaved a a null allele in a zebrafish model of gastrulation phenotypes (Zaghloul_2010) and greatly disrupted MKKS protein interactions (e.g., Rachel_2012, Seo_1010). Five ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; four submitters classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.0

.;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

8.6

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.92

ClinPred

0.69

GERP RS

5.7

Varity_R

0.83

gMVP

0.90

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over