rs201845569

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_017777.4(MKS1):c.874A>G(p.Lys292Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. K292R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

MKS1
NM_017777.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.82

Publications

1 publications found

Variant links:

Genes affected

MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MKS1 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Meckel syndrome, type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
Bardet-Biedl syndrome 13
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
Joubert syndrome 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MKS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0133624375).

BP6

Variant 17-58212419-T-C is Benign according to our data. Variant chr17-58212419-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260888.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017777.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKS1	NM_017777.4	MANE Select	c.874A>G	p.Lys292Glu	missense	Exon 9 of 18	NP_060247.2	Q9NXB0-1
MKS1	NM_001321269.2		c.874A>G	p.Lys292Glu	missense	Exon 9 of 17	NP_001308198.1	A0A7I2V2M0
MKS1	NM_001330397.2		c.874A>G	p.Lys292Glu	missense	Exon 9 of 16	NP_001317326.1	H0Y2S2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKS1	ENST00000393119.7	TSL:1 MANE Select	c.874A>G	p.Lys292Glu	missense	Exon 9 of 18	ENSP00000376827.2	Q9NXB0-1
MKS1	ENST00000537529.7	TSL:1	c.445A>G	p.Lys149Glu	missense	Exon 9 of 18	ENSP00000442096.3	A0A0S2Z5Z2
MKS1	ENST00000966002.1		c.874A>G	p.Lys292Glu	missense	Exon 9 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000176

AC:

AN:

249588

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112004

Other (OTH)

AF:

0.000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000479

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

41572

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000751

Hom.:

Bravo

AF:

0.000616

ESP6500AA

AF:

0.00324

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Meckel syndrome, type 1 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

0.058

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.018

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.1

PhyloP100

7.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.82

REVEL

Benign

0.17

Sift

Benign

0.42

Sift4G

Benign

0.91

Polyphen

0.0

Vest4

0.68

MVP

0.72

MPC

0.36

ClinPred

0.10

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.46

Mutation Taster

=70/30

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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