rs1555600644

Variant names:

• chr17-58216279-CATTATAATACATCAAACTTTTGCTTCTGTAACTGTTTAATCAAATCAGTTCTACAGAACTGATGCTATCTGACATGTTTTCATAACCAACACTAAACTAATGAATGGCAGGGGAACCAAGAACATTAGAGCTAAAAGGAACCA-C
• rs1555600644
• NM_017777.4:c.262-179_262-37del

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_017777.4(MKS1):​c.262-179_262-37del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.05
• Publications: 0 publications found

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):

• Bardet-Biedl syndrome 13

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 17-58216279-CATTATAATACATCAAACTTTTGCTTCTGTAACTGTTTAATCAAATCAGTTCTACAGAACTGATGCTATCTGACATGTTTTCATAACCAACACTAAACTAATGAATGGCAGGGGAACCAAGAACATTAGAGCTAAAAGGAACCA-C is Pathogenic according to our data. Variant chr17-58216279-CATTATAATACATCAAACTTTTGCTTCTGTAACTGTTTAATCAAATCAGTTCTACAGAACTGATGCTATCTGACATGTTTTCATAACCAACACTAAACTAATGAATGGCAGGGGAACCAAGAACATTAGAGCTAAAAGGAACCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 217674.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	NM_017777.4	MANE Select	c.262-179_262-37del		intron	N/A	NP_060247.2	Q9NXB0-1
	MKS1	NM_001321269.2		c.262-179_262-37del		intron	N/A	NP_001308198.1	A0A7I2V2M0
	MKS1	NM_001330397.2		c.262-179_262-37del		intron	N/A	NP_001317326.1	H0Y2S2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.262-179_262-37del		intron	N/A	ENSP00000376827.2	Q9NXB0-1
	MKS1	ENST00000537529.7	TSL:1	c.-168-179_-168-37del		intron	N/A	ENSP00000442096.3	A0A0S2Z5Z2
	MKS1	ENST00000966002.1		c.262-179_262-37del		intron	N/A	ENSP00000636061.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
BranchPoint Hunter		3.0
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555600644; hg19: chr17-56293640;