chr17-58207883-C-T

Variant names:

• chr17-58207883-C-T
• rs16942826
• NM_017777.4:c.1273+11G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017777.4(MKS1):​c.1273+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,610,336 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.57
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-58207883-C-T is Benign according to our data. Variant chr17-58207883-C-T is described in ClinVar as Benign. ClinVar VariationId is 260880.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 = 0.0121 (1837/152266) while in subpopulation AFR AF = 0.042 (1743/41546). AF 95% confidence interval is 0.0403. There are 49 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 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.1273+11G>A		intron	N/A	NP_060247.2
	MKS1	NM_001321269.2		c.1273+11G>A		intron	N/A	NP_001308198.1
	MKS1	NM_001330397.2		c.1273+11G>A		intron	N/A	NP_001317326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.1273+11G>A		intron	N/A	ENSP00000376827.2
	MKS1	ENST00000537529.7	TSL:1	c.844+11G>A		intron	N/A	ENSP00000442096.3
	MKS1	ENST00000872460.1		c.1284G>A	p.Ser428Ser	synonymous	Exon 14 of 17	ENSP00000542519.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1817 AN: 152148 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00329 AC: 818 AN: 248936 AF XY: 0.00261

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00127 AC: 1846 AN: 1458070 Hom.: 33 Cov.: 32 AF XY: 0.00108 AC XY: 786 AN XY: 725658

African (AFR) AF: 0.0406 AC: 1356 AN: 33384

American (AMR) AF: 0.00338 AC: 151 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26106

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

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00246 AC: 14 AN: 5688

European-Non Finnish (NFE) AF: 0.0000794 AC: 88 AN: 1108700

Other (OTH) AF: 0.00307 AC: 185 AN: 60244

GnomAD4 genome AF: 0.0121 AC: 1837 AN: 152266 Hom.: 49 Cov.: 32 AF XY: 0.0119 AC XY: 886 AN XY: 74454

African (AFR) AF: 0.0420 AC: 1743 AN: 41546

American (AMR) AF: 0.00451 AC: 69 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00297 Hom.: 2

Bravo AF: 0.0142

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome 13 (1)
-	-	1	Meckel syndrome, type 1 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.51
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs16942826; hg19: chr17-56285244;