17-58218692-G-A

Variant names:

• chr17-58218692-G-A
• rs199832333
• NM_017777.4:c.118C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001321269.2(MKS1):​c.118C>T​(p.His40Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000657 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: MKS1 NM_001321269.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 4.80
• Publications: 4 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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 17-58218692-G-A is Benign according to our data. Variant chr17-58218692-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281544.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321269.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	NM_017777.4	MANE Select	c.118C>T	p.His40Tyr	missense	Exon 2 of 18	NP_060247.2
	MKS1	NM_001321269.2		c.118C>T	p.His40Tyr	missense	Exon 2 of 17	NP_001308198.1
	MKS1	NM_001330397.2		c.118C>T	p.His40Tyr	missense	Exon 2 of 16	NP_001317326.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.118C>T	p.His40Tyr	missense	Exon 2 of 18	ENSP00000376827.2
	MKS1	ENST00000537529.7	TSL:1	c.-312C>T		5_prime_UTR	Exon 2 of 18	ENSP00000442096.3
	MKS1	ENST00000966002.1		c.118C>T	p.His40Tyr	missense	Exon 2 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000397 AC: 99 AN: 249588 AF XY: 0.000450

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000777

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000681 AC: 996 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.000696 AC XY: 506 AN XY: 727170

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000224 AC: 10 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000848 AC: 943 AN: 1111926

Other (OTH) AF: 0.000596 AC: 36 AN: 60392

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74432

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.000719 AC: 11 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0165 Hom.: 2344

Bravo AF: 0.000589

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.000839 AC: 7

ExAC AF: 0.000413 AC: 50

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 (1)
-	1	-	Meckel syndrome, type 1 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	1	-	MKS1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.13	B
Vest4		0.25
MVP		0.72
MPC		0.30
ClinPred		0.039	T
GERP RS		5.3
PromoterAI		0.0087	Neutral
Varity_R		0.090
gMVP		0.31
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 37

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

Other links and lift over

dbSNP: rs199832333; hg19: chr17-56296053; COSMIC: COSV108826849; COSMIC: COSV108826849;