rs113994196

Positions:

• chr20-10412638-A-ACAGG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_170784.3(MKKS):​c.876_877insCCTG​(p.Cys293ProfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L292L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MKKS NM_170784.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.152

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-10412638-A-ACAGG is Pathogenic according to our data. Variant chr20-10412638-A-ACAGG is described in ClinVar as [Pathogenic]. Clinvar id is 21672.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKKS	NM_170784.3	c.876_877insCCTG	p.Cys293ProfsTer35	frameshift_variant	3/6	ENST00000347364.7
MKKS	NM_018848.3	c.876_877insCCTG	p.Cys293ProfsTer35	frameshift_variant	3/6
MKKS	NR_072977.2	n.347-3836_347-3835insCCTG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKKS	ENST00000347364.7	c.876_877insCCTG	p.Cys293ProfsTer35	frameshift_variant	3/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6	c.876_877insCCTG	p.Cys293ProfsTer35	frameshift_variant	3/6	1		P1
MKKS	ENST00000651692.1	c.876_877insCCTG	p.Cys293ProfsTer35	frameshift_variant	4/7			P1
MKKS	ENST00000652676.1	n.520_521insCCTG		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Oct 13, 2009

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113994196; hg19: chr20-10393286;