17-58206465-C-T

Variant names:

• chr17-58206465-C-T
• rs386834045
• NM_017777.4:c.1490G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_017777.4(MKS1):​c.1490G>A​(p.Arg497Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKS1 NM_017777.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.12
• Publications: 3 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):

• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58206447-GAGGGCCAAGTCACTCACCT-CTGCTGCAGACAGTGCAAGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2954282.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 17-58206465-C-T is Pathogenic according to our data. Variant chr17-58206465-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56618.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.1490G>A	p.Arg497Lys	missense_variant, splice_region_variant	Exon 16 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.1490G>A	p.Arg497Lys	missense_variant, splice_region_variant	Exon 16 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.056
Sift	Benign	0.25	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.021	B;.
Vest4		0.32
MutPred		0.35		Gain of methylation at R497 (P = 0.0188);.;
MVP		0.81
MPC		0.26
ClinPred		0.68	D
GERP RS		4.1
Varity_R		0.21
gMVP		0.65
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs386834045; hg19: chr17-56283826;