rs145342800

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_170784.3(MKKS):c.1015A>G(p.Ile339Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 1,613,792 control chromosomes in the GnomAD database, including 26 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 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 25 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13O:1

Conservation

PhyloP100: -1.55

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009791404).

BS2

High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MKKS	NM_170784.3 linkuse as main transcript	c.1015A>G	p.Ile339Val	missense_variant	4/6	ENST00000347364.7
MKKS	NM_018848.3 linkuse as main transcript	c.1015A>G	p.Ile339Val	missense_variant	4/6
MKKS	NR_072977.2 linkuse as main transcript	n.376A>G		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.1015A>G	p.Ile339Val	missense_variant	4/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.1015A>G	p.Ile339Val	missense_variant	4/6	1		P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.1015A>G	p.Ile339Val	missense_variant	5/7			P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.659A>G		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00744

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00422

AC:

1059

AN:

251086

Hom.:

AF XY:

0.00453

AC XY:

615

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00585

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00504

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.00422

AC:

6174

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

3154

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00564

Gnomad4 FIN exome

AF:

0.00815

Gnomad4 NFE exome

AF:

0.00429

Gnomad4 OTH exome

AF:

0.00396

GnomAD4 genome

AF:

0.00364

AC:

554

AN:

152322

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

270

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00744

Gnomad4 NFE

AF:

0.00504

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00455

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00430

AC:

522

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2015	- -

not provided

Benign:4Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MKKS: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	This variant is associated with the following publications: (PMID: 22025579, 22090721, 29221435, 18094050, 20498079, 12107442, 15770229, 29127258, 29343940, 20177705) -

McKusick-Kaufman syndrome

Uncertain:2Benign: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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	research	Tolun Lab, Human Genetics Laboratory, Bogazici University	-	- -

Bardet-Biedl syndrome 6

Uncertain:1Benign:1

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Bardet-biedl syndrome 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

Cadd

Benign

0.074

Dann

Benign

0.63

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.085

M_CAP

Benign

0.029

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.57

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.52

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.42

T;T

Sift4G

Benign

0.82

T;T

Polyphen

0.0080

B;B

Vest4

0.66

MVP

0.46

MPC

0.093

ClinPred

0.012

GERP RS

-4.9

Varity_R

0.021

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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