rs2302313

Variant names:

• chr17-58205665-G-A
• rs2302313
• NM_017777.4:c.*414C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017777.4(MKS1):​c.*414C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 1,309,414 control chromosomes in the GnomAD database, including 6,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (590 hom., cov: 32)
  • Exomes 𝑓: 0.10 (6026 hom.)
• Consequence: MKS1 NM_017777.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.67
• Publications: 15 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=-0.9).
• BP6: Variant 17-58205665-G-A is Benign according to our data. Variant chr17-58205665-G-A is described in ClinVar as [Benign]. Clinvar id is 324154.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.*414C>T		3_prime_UTR_variant	Exon 18 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.*414C>T		3_prime_UTR_variant	Exon 18 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12674 AN: 152006 Hom.: 591 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0877

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0963

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0911

GnomAD2 exomes AF: 0.0918 AC: 13946 AN: 151976 AF XY: 0.0944

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.0517

Gnomad ASJ exome AF: 0.0799

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.101 AC: 116446 AN: 1157290 Hom.: 6026 Cov.: 31 AF XY: 0.101 AC XY: 57287 AN XY: 567526

African (AFR) AF: 0.0423 AC: 1043 AN: 24642

American (AMR) AF: 0.0515 AC: 1462 AN: 28406

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 1313 AN: 16208

East Asian (EAS) AF: 0.114 AC: 1495 AN: 13150

South Asian (SAS) AF: 0.112 AC: 8513 AN: 76256

European-Finnish (FIN) AF: 0.0935 AC: 2578 AN: 27568

Middle Eastern (MID) AF: 0.0757 AC: 336 AN: 4438

European-Non Finnish (NFE) AF: 0.103 AC: 95638 AN: 924630

Other (OTH) AF: 0.0969 AC: 4068 AN: 41992

GnomAD4 genome AF: 0.0833 AC: 12677 AN: 152124 Hom.: 590 Cov.: 32 AF XY: 0.0848 AC XY: 6307 AN XY: 74350

African (AFR) AF: 0.0429 AC: 1780 AN: 41506

American (AMR) AF: 0.0682 AC: 1042 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 304 AN: 3468

East Asian (EAS) AF: 0.106 AC: 546 AN: 5154

South Asian (SAS) AF: 0.118 AC: 567 AN: 4822

European-Finnish (FIN) AF: 0.0963 AC: 1018 AN: 10568

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7129 AN: 68006

Other (OTH) AF: 0.0906 AC: 191 AN: 2108

Alfa AF: 0.0967 Hom.: 1606

Bravo AF: 0.0790

Asia WGS AF: 0.0980 AC: 343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome 13 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.46
PhyloP100		-3.7
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: rs2302313; hg19: chr17-56283026; COSMIC: COSV56594743; COSMIC: COSV56594743;