Genetic Variant MKS1:p.Thr62Ser (chr17-58218626-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017777.4(MKS1):c.184A>T(p.Thr62Ser) variant causes a missense 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T62A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

MKS1
NM_017777.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.564

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026297748).

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.184A>T	p.Thr62Ser	missense	Exon 2 of 18	NP_060247.2	Q9NXB0-1
MKS1	NM_001321269.2		c.184A>T	p.Thr62Ser	missense	Exon 2 of 17	NP_001308198.1	A0A7I2V2M0
MKS1	NM_001330397.2		c.184A>T	p.Thr62Ser	missense	Exon 2 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.184A>T	p.Thr62Ser	missense	Exon 2 of 18	ENSP00000376827.2	Q9NXB0-1
MKS1	ENST00000537529.7	TSL:1	c.-246A>T		5_prime_UTR	Exon 2 of 18	ENSP00000442096.3	A0A0S2Z5Z2
LPO	ENST00000582328.5	TSL:5	c.-480T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000464636.1	P22079-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.6

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.14

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.58

M_CAP

Benign

0.0081

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.41

PhyloP100

-0.56

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.14

REVEL

Benign

0.039

Sift

Benign

0.45

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.11

MutPred

0.13

Loss of glycosylation at T62 (P = 0.0645)

MVP

0.51

MPC

0.22

ClinPred

0.047

GERP RS

-4.3

PromoterAI

-0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.17

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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