rs386834051

Variant names:

• chr17-58219175-T-TCCCGG
• rs386834051
• NM_017777.4:c.51_55dupCCGGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MKS1 NM_017777.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.05

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]

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]

ENSG00000287337 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 38 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 [Likely_pathogenic]. Clinvar id is 56625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift_variant	Exon 1 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.51_55dupCCGGG	p.Asp19AlafsTer36	frameshift_variant	Exon 1 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81094

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 SAS 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: 4 AN: 1398944 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1

May 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56625). This variant is also known as 50insCCGGG, P17fsX163. This premature translational stop signal has been observed in individual(s) with Meckel syndrome (PMID: 16415886). This variant is present in population databases (rs386834051, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Asp19Alafs*36) in the MKS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MKS1 are known to be pathogenic (PMID: 19466712, 24886560, 26490104). -

Meckel syndrome, type 1 Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Bardet-Biedl syndrome 13 Pathogenic:1

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 13, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834051; hg19: chr17-56296536;