rs113994195

Variant names:

• chr20-10413073-GAGTACTACTAA-G
• rs113994195
• NM_170784.3:c.431_441delTTAGTAGTACT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_170784.3(MKKS):​c.431_441delTTAGTAGTACT​(p.Phe144SerfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F144F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MKKS NM_170784.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.69
• Publications: 1 publications found

Genes affected

MKKS (HGNC:7108): (MKKS centrosomal shuttling protein) This gene encodes a protein which shares sequence similarity with other members of the type II chaperonin family. The encoded protein is a centrosome-shuttling protein and plays an important role in cytokinesis. This protein also interacts with other type II chaperonin members to form a complex known as the BBSome, which involves ciliary membrane biogenesis. This protein is encoded by a downstream open reading frame (dORF). Several upstream open reading frames (uORFs) have been identified, which repress the translation of the dORF, and two of which can encode small mitochondrial membrane proteins. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 6, also known as McKusick-Kaufman syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2023]

MKKS Gene-Disease associations (from GenCC):

• McKusick-Kaufman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Bardet-Biedl syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-10413073-GAGTACTACTAA-G is Pathogenic according to our data. Variant chr20-10413073-GAGTACTACTAA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 21670.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKKS	NM_170784.3	c.431_441delTTAGTAGTACT	p.Phe144SerfsTer9	frameshift_variant	Exon 3 of 6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.431_441delTTAGTAGTACT	p.Phe144SerfsTer9	frameshift_variant	Exon 3 of 6		NP_061336.1
MKKS	NR_072977.2	n.347-4281_347-4271delTTAGTAGTACT		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.431_441delTTAGTAGTACT	p.Phe144SerfsTer9	frameshift_variant	Exon 3 of 6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.431_441delTTAGTAGTACT	p.Phe144SerfsTer9	frameshift_variant	Exon 3 of 6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.431_441delTTAGTAGTACT	p.Phe144SerfsTer9	frameshift_variant	Exon 4 of 7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.459-384_459-374delTTAGTAGTACT		intron_variant	Intron 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:1

Oct 13, 2009

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113994195; hg19: chr20-10393721;