dbSNP rs372527189: MKS1:c.515+12C>T (chr17-58214729-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001321269.2(MKS1):c.515+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,603,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 3 hom. )

Consequence

MKS1
NM_001321269.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.382

Publications

0 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):

Meckel syndrome, type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-58214729-G-A is Benign according to our data. Variant chr17-58214729-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260885.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000432 (627/1451030) while in subpopulation MID AF = 0.0118 (68/5766). AF 95% confidence interval is 0.00954. There are 3 homozygotes in GnomAdExome4. There are 328 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

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	Effect	Exon Rank	Protein
MKS1	NM_017777.4	MANE Select	c.515+12C>T	intron	N/A	NP_060247.2
MKS1	NM_001321269.2		c.515+12C>T	intron	N/A	NP_001308198.1
MKS1	NM_001330397.2		c.515+12C>T	intron	N/A	NP_001317326.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MKS1	ENST00000393119.7	TSL:1 MANE Select	c.515+12C>T	intron	N/A	ENSP00000376827.2
MKS1	ENST00000537529.7	TSL:1	c.86+12C>T	intron	N/A	ENSP00000442096.3
MKS1	ENST00000966002.1		c.515+12C>T	intron	N/A	ENSP00000636061.1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000641

AC:

154

AN:

240228

AF XY:

0.000642

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00268

GnomAD4 exome

AF:

0.000432

AC:

627

AN:

1451030

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

328

AN XY:

722026

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33410

American (AMR)

AF:

0.00193

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.000498

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.000373

AC:

AN:

85720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44610

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000304

AC:

338

AN:

1111016

Other (OTH)

AF:

0.00129

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000394

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41540

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000726

Hom.:

Bravo

AF:

0.000484

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Bardet-Biedl syndrome 13 (1)

Meckel syndrome, type 1 (1)

Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.9

(source)

DANN

Benign

0.82

PhyloP100

-0.38

PromoterAI

0.0020

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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