rs149051148

Positions:

chr20-10405407-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_170784.3(MKKS):c.1553G>A(p.Arg518His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 0.0140

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015246242).

BP6

Variant 20-10405407-C-T is Benign according to our data. Variant chr20-10405407-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215903.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=4, Likely_benign=1}. Variant chr20-10405407-C-T is described in Lovd as [Benign]. Variant chr20-10405407-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MKKS	NM_170784.3 linkuse as main transcript	c.1553G>A	p.Arg518His	missense_variant	6/6	ENST00000347364.7
MKKS	NM_018848.3 linkuse as main transcript	c.1553G>A	p.Arg518His	missense_variant	6/6
MKKS	NR_072977.2 linkuse as main transcript	n.914G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.1553G>A	p.Arg518His	missense_variant	6/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.1553G>A	p.Arg518His	missense_variant	6/6	1		P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.1553G>A	p.Arg518His	missense_variant	7/7			P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.1197G>A		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000306

AC:

AN:

251430

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000272

AC:

398

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

221

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000286

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000164

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000206

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MKKS: PM2, BP4 -
Likely benign, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MKKS p.Arg518His variant was identified in 1 of 163 pedigrees with Bardet-Biedl syndrome (Beales_2001_PMID:11179009). The variant was also identified in dbSNP (ID: rs149051148), ClinVar (classified as likely benign by Invitae) and LOVD 3.0 (classified as likely benign and benign). The variant was identified in control databases in 82 of 282826 chromosomes at a frequency of 0.00029 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 14 of 19954 chromosomes (freq: 0.000702), European (non-Finnish) in 54 of 129138 chromosomes (freq: 0.000418), South Asian in 10 of 30616 chromosomes (freq: 0.000327) and Latino in 4 of 35430 chromosomes (freq: 0.000113), while the variant was not observed in the African, Ashkenazi Jewish, European (Finnish), and Other populations. Functional studies of the R518H variant show no effect on the protein compared to wildtype (Hirayama_2008_PMID:18094050; Zaghloul_2010_PMID:20498079). The p.Arg518 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

McKusick-Kaufman syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

MKKS-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The MKKS c.1553G>A variant is predicted to result in the amino acid substitution p.Arg518His. This variant was reported in one patient with Bardet-Biedl syndrome (Beales et al. 2001. PubMed ID: 11179009). Functional studies suggest that the p.Arg518His variant does not increase protein degradation or solubility (Hirayama et al. 2008. PubMed ID: 18094050). In another study, the p.Arg518His variant is predicted to be benign (Zaghloul et al. 2010. PubMed ID: 20498079, reported as BBS6 p.Arg518His, Table S5). This variant is reported in 0.070% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10386055-C-T). It's frequency in gnomAD is higher than expected for a pathogenic change in this gene. In ClinVar it has classifications of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/215903/). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Benign

5.9

DANN

Benign

0.73

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.19

.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-2.6

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

1.9

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.86

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0

B;B

Vest4

0.041

MVP

0.52

MPC

0.13

ClinPred

0.041

GERP RS

-4.8

Varity_R

0.011

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over