NM_017777.4:c.233T>G

Variant names:

• chr17-58216694-A-C
• rs786204222
• NM_017777.4:c.233T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_017777.4(MKS1):​c.233T>G​(p.Ile78Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKS1 NM_017777.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.79
• 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):

• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 17-58216694-A-C is Pathogenic according to our data. Variant chr17-58216694-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 188334.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.233T>G	p.Ile78Ser	missense_variant	Exon 3 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.233T>G	p.Ile78Ser	missense_variant	Exon 3 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1

Dec 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with serine at codon 78 of the MKS1 protein (p.Ile78Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Joubert syndrome (Invitae). In at least one of these individuals, it was determined to be on the opposite chromosome (in trans) from a pathogenic MKS1 variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -

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

Mar 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.82
MutPred		0.56		Gain of disorder (P = 0.0025);Gain of disorder (P = 0.0025);.;
MVP		0.89
MPC		0.58
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.78
Mutation Taster		=62/38	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs786204222; hg19: chr17-56294055;