rs764266

Variant names:

• chr20-10408832-T-A
• rs764266
• NM_170784.3:c.986-29A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170784.3(MKKS):​c.986-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,565,076 control chromosomes in the GnomAD database, including 17,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3387 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13816 hom.)
• Consequence: MKKS NM_170784.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.346
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-10408832-T-A is Benign according to our data. Variant chr20-10408832-T-A is described in ClinVar as Benign. ClinVar VariationId is 261061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 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.986-29A>T		intron	N/A	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.986-29A>T		intron	N/A	NP_061336.1	Q9NPJ1
	MKKS	NR_072977.2		n.347-29A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.986-29A>T		intron	N/A	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000399054.6	TSL:1	c.986-29A>T		intron	N/A	ENSP00000382008.2	Q9NPJ1
	MKKS	ENST00000651692.1		c.986-29A>T		intron	N/A	ENSP00000498849.1	Q9NPJ1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28116 AN: 152006 Hom.: 3380 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.152 AC: 36553 AN: 239872 AF XY: 0.153

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.130 AC: 183011 AN: 1412950 Hom.: 13816 Cov.: 26 AF XY: 0.132 AC XY: 92789 AN XY: 705022

African (AFR) AF: 0.340 AC: 11078 AN: 32536

American (AMR) AF: 0.119 AC: 5257 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2638 AN: 25642

East Asian (EAS) AF: 0.245 AC: 9664 AN: 39440

South Asian (SAS) AF: 0.241 AC: 20359 AN: 84436

European-Finnish (FIN) AF: 0.116 AC: 6056 AN: 52116

Middle Eastern (MID) AF: 0.146 AC: 687 AN: 4710

European-Non Finnish (NFE) AF: 0.111 AC: 118872 AN: 1071220

Other (OTH) AF: 0.143 AC: 8400 AN: 58596

GnomAD4 genome AF: 0.185 AC: 28155 AN: 152126 Hom.: 3387 Cov.: 32 AF XY: 0.190 AC XY: 14103 AN XY: 74384

African (AFR) AF: 0.332 AC: 13792 AN: 41482

American (AMR) AF: 0.170 AC: 2597 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3466

East Asian (EAS) AF: 0.243 AC: 1255 AN: 5172

South Asian (SAS) AF: 0.237 AC: 1144 AN: 4826

European-Finnish (FIN) AF: 0.119 AC: 1257 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7337 AN: 67992

Other (OTH) AF: 0.164 AC: 346 AN: 2108

Alfa AF: 0.141 Hom.: 359

Bravo AF: 0.191

Asia WGS AF: 0.220 AC: 762 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	McKusick-Kaufman syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.55
PhyloP100		0.35
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: rs764266; hg19: chr20-10389480; COSMIC: COSV61398195; COSMIC: COSV61398195;