17-58208542-G-C

Variant names:

• chr17-58208542-G-C
• NM_017777.4:c.1066C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_017777.4(MKS1):​c.1066C>G​(p.Gln356Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MKS1 NM_017777.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.14

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain C2 B9-type (size 128) in uniprot entity MKS1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_017777.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.1066C>G	p.Gln356Glu	missense_variant	Exon 12 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.1066C>G	p.Gln356Glu	missense_variant	Exon 12 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.013	D;.;D;.
Sift4G	Benign	0.099	T;D;T;D
Polyphen		0.99	D;.;.;.
Vest4		0.79
MutPred		0.74		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;
MVP		0.95
MPC		0.93
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-56285903;