rs6133917

Positions:

• chr20-10412514-A-C
• chr20-10412514-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170784.3(MKKS):​c.985+16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,611,466 control chromosomes in the GnomAD database, including 14,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1778 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12573 hom.)
• Consequence: MKKS NM_170784.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0780

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-10412514-A-C is Benign according to our data. Variant chr20-10412514-A-C is described in ClinVar as [Benign]. Clinvar id is 196492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10412514-A-C is described in Lovd as [Benign]. Variant chr20-10412514-A-C is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKKS	NM_170784.3	c.985+16T>G		intron_variant		ENST00000347364.7
MKKS	NM_018848.3	c.985+16T>G		intron_variant
MKKS	NR_072977.2	n.347-3711T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKKS	ENST00000347364.7	c.985+16T>G		intron_variant		1	NM_170784.3	P1
MKKS	ENST00000399054.6	c.985+16T>G		intron_variant		1		P1
MKKS	ENST00000651692.1	c.985+16T>G		intron_variant				P1
MKKS	ENST00000652676.1	n.629+16T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21919 AN: 152096 Hom.: 1773 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.140 AC: 35060 AN: 249660 Hom.: 2923 AF XY: 0.144 AC XY: 19418 AN XY: 135092

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0999

Gnomad EAS exome AF: 0.233

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.124 AC: 181139 AN: 1459252 Hom.: 12573 Cov.: 32 AF XY: 0.127 AC XY: 92124 AN XY: 726090

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.144 AC: 21946 AN: 152214 Hom.: 1778 Cov.: 32 AF XY: 0.150 AC XY: 11156 AN XY: 74442

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.133

Alfa AF: 0.0935 Hom.: 228

Bravo AF: 0.144

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.5
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs6133917; hg19: chr20-10393162; COSMIC: COSV61398022; COSMIC: COSV61398022;