rs145342800

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I339L) has been classified as Uncertain significance.

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

Publications

16 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
MKKS-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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: Benign. The variant received -9 ACMG points.

BP4

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

BP6

Variant 20-10408774-T-C is Benign according to our data. Variant chr20-10408774-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100586.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKKS	NM_170784.3	MANE Select	c.1015A>G	p.Ile339Val	missense	Exon 4 of 6	NP_740754.1	Q9NPJ1
MKKS	NM_018848.3		c.1015A>G	p.Ile339Val	missense	Exon 4 of 6	NP_061336.1	Q9NPJ1
MKKS	NR_072977.2		n.376A>G		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKKS	ENST00000347364.7	TSL:1 MANE Select	c.1015A>G	p.Ile339Val	missense	Exon 4 of 6	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6	TSL:1	c.1015A>G	p.Ile339Val	missense	Exon 4 of 6	ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1		c.1015A>G	p.Ile339Val	missense	Exon 5 of 7	ENSP00000498849.1	Q9NPJ1

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

GnomAD2 exomes

AF:

0.00422

AC:

1059

AN:

251086

AF XY:

0.00453

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 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

African (AFR)

AF:

0.000538

AC:

AN:

33474

American (AMR)

AF:

0.00244

AC:

109

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39668

South Asian (SAS)

AF:

0.00564

AC:

486

AN:

86234

European-Finnish (FIN)

AF:

0.00815

AC:

435

AN:

53378

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00429

AC:

4773

AN:

1111736

Other (OTH)

AF:

0.00396

AC:

239

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

286

572

859

1145

1431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.00364

AC:

554

AN:

152322

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

270

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41576

American (AMR)

AF:

0.00477

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00744

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00504

AC:

343

AN:

68032

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00445

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (5)

McKusick-Kaufman syndrome (3)

Bardet-Biedl syndrome 6 (2)

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

0.074

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.32

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.59

M_CAP

Benign

0.029

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.57

PhyloP100

-1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.52

REVEL

Uncertain

0.49

Sift

Benign

0.42

Sift4G

Benign

0.82

Polyphen

0.0080

Vest4

0.66

MVP

0.46

MPC

0.093

ClinPred

0.012

GERP RS

-4.9

Varity_R

0.021

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over