20-10434132-C-CCAGGCCGCCACAGGCCGCCA

Variant names:

• chr20-10434132-C-CCAGGCCGCCACAGGCCGCCA
• rs16996729
• NM_170784.3:c.-674_-673insTGGCGGCCTGTGGCGGCCTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_170784.3(MKKS):​c.-674_-673insTGGCGGCCTGTGGCGGCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,202 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: MKKS NM_170784.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 2 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• MKKS-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

LOC128706665 (HGNC:0):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170784.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	NM_170784.3	MANE Select	c.-674_-673insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 6	NP_740754.1	Q9NPJ1
	LOC128706665	NM_001394148.2	MANE Select	c.-47_-46insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	NP_001381077.1
	LOC128706666	NM_001394149.2	MANE Select	c.-301_-300insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	NP_001381078.1	V9GZ13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-674_-673insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 6	ENSP00000246062.4	Q9NPJ1
	ENSG00000285723	ENST00000649912.2	MANE Select	c.-47_-46insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	ENSP00000497510.1	Q9HB66
	ENSG00000285508	ENST00000713549.1	MANE Select	c.-301_-300insTGGCGGCCTGTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	ENSP00000518845.1	V9GZ13

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.7

Splicing

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

Other links and lift over

dbSNP: rs16996729; hg19: chr20-10414780;