rs587777827

Variant names:

• chr20-10413233-GA-G
• rs587777827
• NM_170784.3:c.281delT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_170784.3(MKKS):​c.281delT​(p.Phe94SerfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MKKS NM_170784.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.63

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 18 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 20-10413233-GA-G is Pathogenic according to our data. Variant chr20-10413233-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 5313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10413233-GA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKKS	NM_170784.3	c.281delT	p.Phe94SerfsTer9	frameshift_variant	Exon 3 of 6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.281delT	p.Phe94SerfsTer9	frameshift_variant	Exon 3 of 6		NP_061336.1
MKKS	NR_072977.2	n.347-4431delT		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.281delT	p.Phe94SerfsTer9	frameshift_variant	Exon 3 of 6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.281delT	p.Phe94SerfsTer9	frameshift_variant	Exon 3 of 6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.281delT	p.Phe94SerfsTer9	frameshift_variant	Exon 4 of 7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.459-534delT		intron_variant	Intron 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

McKusick-Kaufman syndrome;C1858054:Bardet-Biedl syndrome 6 Pathogenic:1

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome Pathogenic:1

Apr 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe94Serfs*9) in the MKKS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MKKS are known to be pathogenic (PMID: 11179009, 28761321, 30614526). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10973251). This variant is also known as 280∆T (F94fsX103). ClinVar contains an entry for this variant (Variation ID: 5313). For these reasons, this variant has been classified as Pathogenic. -

Bardet-Biedl syndrome 6 Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777827; hg19: chr20-10393881;