rs116514023

Variant names:

• chr17-58219248-G-C
• rs116514023
• NM_017777.4:c.-18C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_017777.4(MKS1):​c.-18C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,549,458 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: MKS1 NM_017777.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0560
• Publications: 1 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]

ENSG00000287337 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-58219248-G-C is Benign according to our data. Variant chr17-58219248-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1737/152338) while in subpopulation AFR AF = 0.0391 (1626/41580). AF 95% confidence interval is 0.0375. There are 34 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	NM_017777.4	MANE Select	c.-18C>G		5_prime_UTR	Exon 1 of 18	NP_060247.2
	MKS1	NM_001321269.2		c.-18C>G		5_prime_UTR	Exon 1 of 17	NP_001308198.1
	MKS1	NM_001330397.2		c.-18C>G		5_prime_UTR	Exon 1 of 16	NP_001317326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.-18C>G		5_prime_UTR	Exon 1 of 18	ENSP00000376827.2
	MKS1	ENST00000537529.7	TSL:1	c.-350+214C>G		intron	N/A	ENSP00000442096.3
	MKS1	ENST00000678463.1		c.-18C>G		5_prime_UTR	Exon 1 of 17	ENSP00000502984.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1737 AN: 152220 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00241 AC: 360 AN: 149572 AF XY: 0.00170

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000519

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00113 AC: 1578 AN: 1397120 Hom.: 25 Cov.: 31 AF XY: 0.000917 AC XY: 632 AN XY: 689176

African (AFR) AF: 0.0420 AC: 1327 AN: 31588

American (AMR) AF: 0.00224 AC: 80 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47550

Middle Eastern (MID) AF: 0.000906 AC: 5 AN: 5518

European-Non Finnish (NFE) AF: 0.0000399 AC: 43 AN: 1078728

Other (OTH) AF: 0.00205 AC: 119 AN: 57946

GnomAD4 genome AF: 0.0114 AC: 1737 AN: 152338 Hom.: 34 Cov.: 32 AF XY: 0.0107 AC XY: 794 AN XY: 74496

African (AFR) AF: 0.0391 AC: 1626 AN: 41580

American (AMR) AF: 0.00536 AC: 82 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00641 Hom.: 6

Bravo AF: 0.0132

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome 13 (1)
-	-	1	Meckel syndrome, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		-0.056
PromoterAI		-0.41	Neutral
Mutation Taster		=295/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs116514023; hg19: chr17-56296609;