NM_017777.4:c.515+12C>T

Variant names:

• chr17-58214729-G-A
• rs372527189
• NM_017777.4:c.515+12C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017777.4(MKS1):​c.515+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,603,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.382
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-58214729-G-A is Benign according to our data. Variant chr17-58214729-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260885.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000432 (627/1451030) while in subpopulation MID AF = 0.0118 (68/5766). AF 95% confidence interval is 0.00954. There are 3 homozygotes in GnomAdExome4. There are 328 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.515+12C>T		intron_variant	Intron 5 of 17	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.515+12C>T		intron_variant	Intron 5 of 17	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000641 AC: 154 AN: 240228 AF XY: 0.000642

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.000432 AC: 627 AN: 1451030 Hom.: 3 Cov.: 30 AF XY: 0.000454 AC XY: 328 AN XY: 722026

African (AFR) AF: 0.000359 AC: 12 AN: 33410

American (AMR) AF: 0.00193 AC: 86 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.000373 AC: 32 AN: 85720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44610

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5766

European-Non Finnish (NFE) AF: 0.000304 AC: 338 AN: 1111016

Other (OTH) AF: 0.00129 AC: 78 AN: 60248

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74430

African (AFR) AF: 0.000144 AC: 6 AN: 41540

American (AMR) AF: 0.00131 AC: 20 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.000484

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Sep 06, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bardet-Biedl syndrome 13 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.82
PhyloP100		-0.38
PromoterAI		0.0020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs372527189; hg19: chr17-56292090;