rs6133922

Variant names:

• chr20-10420425-A-G
• rs6133922
• NM_170784.3:c.-418+103T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170784.3(MKKS):​c.-418+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 152,268 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.067 (370 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MKKS NM_170784.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 10 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):

ENSG00000285508 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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.-418+103T>C		intron	N/A	NP_740754.1	Q9NPJ1
	LOC128706665	NM_001394148.2	MANE Select	c.*18+103T>C		intron	N/A	NP_001381077.1
	LOC128706666	NM_001394149.2	MANE Select	c.-45+103T>C		intron	N/A	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.-418+103T>C		intron	N/A	ENSP00000246062.4	Q9NPJ1
	ENSG00000285723	ENST00000649912.2	MANE Select	c.*18+103T>C		intron	N/A	ENSP00000497510.1	Q9HB66
	ENSG00000285508	ENST00000713549.1	MANE Select	c.-45+103T>C		intron	N/A	ENSP00000518845.1	V9GZ13

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10147 AN: 152150 Hom.: 370 Cov.: 32

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0782

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0703

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0666 AC: 10145 AN: 152268 Hom.: 370 Cov.: 32 AF XY: 0.0686 AC XY: 5111 AN XY: 74458

African (AFR) AF: 0.0706 AC: 2934 AN: 41558

American (AMR) AF: 0.0592 AC: 906 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0782 AC: 271 AN: 3466

East Asian (EAS) AF: 0.168 AC: 870 AN: 5178

South Asian (SAS) AF: 0.135 AC: 649 AN: 4822

European-Finnish (FIN) AF: 0.0440 AC: 467 AN: 10620

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0570 AC: 3879 AN: 68014

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0596 Hom.: 564

Bravo AF: 0.0657

Asia WGS AF: 0.119 AC: 414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.8
DANN	Benign	0.78
PhyloP100		0.0070
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6133922; hg19: chr20-10401073;