rs764266

Positions:

• chr20-10408832-T-A

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.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

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=-0.77).
• BP6: Variant 20-10408832-T-A is Benign according to our data. Variant chr20-10408832-T-A is described in ClinVar as [Benign]. Clinvar id is 261061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10408832-T-A is described in Lovd as [Likely_pathogenic]. Variant chr20-10408832-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3	c.986-29A>T		intron_variant		ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.986-29A>T		intron_variant			NP_061336.1
MKKS	NR_072977.2	n.347-29A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.986-29A>T		intron_variant		1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000399054.6	c.986-29A>T		intron_variant		1		ENSP00000382008	P1
MKKS	ENST00000651692.1	c.986-29A>T		intron_variant				ENSP00000498849	P1
MKKS	ENST00000652676.1	n.630-29A>T		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.152 AC: 36553 AN: 239872 Hom.: 3459 AF XY: 0.153 AC XY: 19881 AN XY: 129968

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 SAS exome AF: 0.249

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

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.143

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.164

Alfa AF: 0.141 Hom.: 359

Bravo AF: 0.191

Asia WGS AF: 0.220 AC: 762 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

McKusick-Kaufman syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.55

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: rs764266; hg19: chr20-10389480; COSMIC: COSV61398195; COSMIC: COSV61398195;