17-58206088-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001321269.2(MKS1):c.1588G>C(p.Gly530Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,611,270 control chromosomes in the GnomAD database, including 1,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G530C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.063 ( 559 hom., cov: 32)

Exomes 𝑓: 0.030 ( 1025 hom. )

Consequence

MKS1
NM_001321269.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.318

Publications

8 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 17-58206088-C-G is Benign according to our data. Variant chr17-58206088-C-G is described in ClinVar as Benign. ClinVar VariationId is 126272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321269.2. 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.1671G>C	p.Leu557Leu	synonymous	Exon 18 of 18	NP_060247.2	Q9NXB0-1
MKS1	NM_001321269.2		c.1588G>C	p.Gly530Arg	missense	Exon 17 of 17	NP_001308198.1	A0A7I2V2M0
MKS1	NM_001321268.2		c.1062G>C	p.Leu354Leu	synonymous	Exon 17 of 17	NP_001308197.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKS1	ENST00000393119.7	TSL:1 MANE Select	c.1671G>C	p.Leu557Leu	synonymous	Exon 18 of 18	ENSP00000376827.2	Q9NXB0-1
MKS1	ENST00000537529.7	TSL:1	c.1242G>C	p.Leu414Leu	synonymous	Exon 18 of 18	ENSP00000442096.3	A0A0S2Z5Z2
MKS1	ENST00000678463.1		c.1588G>C	p.Gly530Arg	missense	Exon 17 of 17	ENSP00000502984.1	A0A7I2V2M0

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9638

AN:

152080

Hom.:

557

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0363

Gnomad ASJ

AF:

0.0671

Gnomad EAS

AF:

0.00791

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.0296

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0657

GnomAD2 exomes

AF:

0.0369

AC:

8919

AN:

241980

AF XY:

0.0353

show subpopulations

Gnomad AFR exome

AF:

0.156

Gnomad AMR exome

AF:

0.0263

Gnomad ASJ exome

AF:

0.0718

Gnomad EAS exome

AF:

0.00635

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0455

GnomAD4 exome

AF:

0.0304

AC:

44418

AN:

1459072

Hom.:

1025

Cov.:

AF XY:

0.0303

AC XY:

21959

AN XY:

725694

show subpopulations

African (AFR)

AF:

0.159

AC:

5322

AN:

33434

American (AMR)

AF:

0.0289

AC:

1281

AN:

44338

Ashkenazi Jewish (ASJ)

AF:

0.0699

AC:

1822

AN:

26056

East Asian (EAS)

AF:

0.0128

AC:

507

AN:

39646

South Asian (SAS)

AF:

0.0291

AC:

2501

AN:

85886

European-Finnish (FIN)

AF:

0.0303

AC:

1606

AN:

52978

Middle Eastern (MID)

AF:

0.0756

AC:

407

AN:

5384

European-Non Finnish (NFE)

AF:

0.0258

AC:

28617

AN:

1111134

Other (OTH)

AF:

0.0391

AC:

2355

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2718

5435

8153

10870

13588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0634

AC:

9645

AN:

152198

Hom.:

559

Cov.:

AF XY:

0.0626

AC XY:

4655

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.153

AC:

6335

AN:

41516

American (AMR)

AF:

0.0363

AC:

555

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

233

AN:

3472

East Asian (EAS)

AF:

0.00793

AC:

AN:

5170

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4814

European-Finnish (FIN)

AF:

0.0296

AC:

314

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0277

AC:

1884

AN:

68008

Other (OTH)

AF:

0.0650

AC:

137

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

442

884

1325

1767

2209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0253

Hom.:

Bravo

AF:

0.0686

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Meckel syndrome, type 1 (3)

not specified (3)

Bardet-Biedl syndrome 13 (2)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.81

(source)

DANN

Benign

0.59

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over