chr17-58219175-T-TCCCGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017777.4(MKS1):c.51_55dupCCGGG(p.Asp19AlafsTer36) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000286 in 1,398,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D19D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

MKS1
NM_017777.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.05

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 links:

LPO (HGNC:6678): (lactoperoxidase) This gene encodes a member of the peroxidase family of proteins. The encoded preproprotein is proteolytically processed to generate the mature enzyme. Following its secretion from salivary, mammary, and other mucosal glands, this enzyme catalyzes the generation of the antimicrobial substance hypothiocyanous acid. This gene is present in a gene cluster on chromosome 17. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

LPO links:

ENSG00000287337 (HGNC:):

ENSG00000287337 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 127 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-58219175-T-TCCCGG is Pathogenic according to our data. Variant chr17-58219175-T-TCCCGG is described in ClinVar as Pathogenic. ClinVar VariationId is 56625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift	Exon 1 of 18	NP_060247.2	Q9NXB0-1
MKS1	NM_001321269.2		c.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift	Exon 1 of 17	NP_001308198.1	A0A7I2V2M0
MKS1	NM_001330397.2		c.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift	Exon 1 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.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift	Exon 1 of 18	ENSP00000376827.2	Q9NXB0-1
MKS1	ENST00000537529.7	TSL:1	c.-350+282_-350+286dupCCGGG		intron	N/A	ENSP00000442096.3	A0A0S2Z5Z2
MKS1	ENST00000966002.1		c.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift	Exon 1 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000657

AC:

AN:

152158

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1398944

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.00

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078978

Other (OTH)

AF:

0.00

AC:

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bardet-Biedl syndrome 13 (1)

Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 (1)

Meckel syndrome, type 1 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=88/212

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over