chr17-58212356-TGCA-T

Variant names:

• chr17-58212356-TGCA-T
• rs3217067
• NM_017777.4:c.915+19_915+21delTGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_017777.4(MKS1):​c.915+19_915+21delTGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 1,613,470 control chromosomes in the GnomAD database, including 8,110 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (576 hom., cov: 31)
  • Exomes 𝑓: 0.10 (7534 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.61
• Publications: 5 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Meckel syndrome, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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 -16 ACMG points.

• BP6: Variant 17-58212356-TGCA-T is Benign according to our data. Variant chr17-58212356-TGCA-T is described in ClinVar as Benign. ClinVar VariationId is 260889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

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.915+19_915+21delTGC		intron	N/A	NP_060247.2	Q9NXB0-1
	MKS1	NM_001321269.2		c.915+19_915+21delTGC		intron	N/A	NP_001308198.1	A0A7I2V2M0
	MKS1	NM_001330397.2		c.915+19_915+21delTGC		intron	N/A	NP_001317326.1	H0Y2S2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.915+19_915+21delTGC		intron	N/A	ENSP00000376827.2	Q9NXB0-1
	MKS1	ENST00000537529.7	TSL:1	c.486+19_486+21delTGC		intron	N/A	ENSP00000442096.3	A0A0S2Z5Z2
	MKS1	ENST00000966002.1		c.915+19_915+21delTGC		intron	N/A	ENSP00000636061.1

Frequencies

GnomAD3 genomes AF: 0.0835 AC: 12704 AN: 152152 Hom.: 577 Cov.: 31

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0685

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0913

GnomAD2 exomes AF: 0.0922 AC: 23016 AN: 249558 AF XY: 0.0955

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0960

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.100 AC: 146230 AN: 1461200 Hom.: 7534 AF XY: 0.101 AC XY: 73140 AN XY: 726942

African (AFR) AF: 0.0445 AC: 1491 AN: 33470

American (AMR) AF: 0.0505 AC: 2259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 2124 AN: 26134

East Asian (EAS) AF: 0.0989 AC: 3924 AN: 39690

South Asian (SAS) AF: 0.112 AC: 9697 AN: 86242

European-Finnish (FIN) AF: 0.0997 AC: 5322 AN: 53402

Middle Eastern (MID) AF: 0.0801 AC: 462 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115189 AN: 1111408

Other (OTH) AF: 0.0955 AC: 5762 AN: 60362

GnomAD4 genome AF: 0.0834 AC: 12706 AN: 152270 Hom.: 576 Cov.: 31 AF XY: 0.0850 AC XY: 6332 AN XY: 74452

African (AFR) AF: 0.0437 AC: 1815 AN: 41556

American (AMR) AF: 0.0684 AC: 1046 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 305 AN: 3472

East Asian (EAS) AF: 0.103 AC: 532 AN: 5180

South Asian (SAS) AF: 0.118 AC: 570 AN: 4824

European-Finnish (FIN) AF: 0.0957 AC: 1015 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7132 AN: 68016

Other (OTH) AF: 0.0908 AC: 192 AN: 2114

Alfa AF: 0.0909 Hom.: 102

Bravo AF: 0.0792

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs3217067; hg19: chr17-56289717;