rs61734546

chr20-10405498-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_170784.3(MKKS):c.1462G>A(p.Ala488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,142 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A488I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.223

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 (MetaRNN=0.0028983653).
• BP6: Variant 20-10405498-C-T is Benign according to our data. Variant chr20-10405498-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10405498-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1669/152266) while in subpopulation AFR AF= 0.0385 (1597/41532). AF 95% confidence interval is 0.0369. There are 29 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKKS	NM_170784.3	c.1462G>A	p.Ala488Thr	missense_variant	6/6	ENST00000347364.7
MKKS	NM_018848.3	c.1462G>A	p.Ala488Thr	missense_variant	6/6
MKKS	NR_072977.2	n.823G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKKS	ENST00000347364.7	c.1462G>A	p.Ala488Thr	missense_variant	6/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6	c.1462G>A	p.Ala488Thr	missense_variant	6/6	1		P1
MKKS	ENST00000651692.1	c.1462G>A	p.Ala488Thr	missense_variant	7/7			P1
MKKS	ENST00000652676.1	n.1106G>A		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1667 AN: 152148 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00280 AC: 705 AN: 251394 Hom.: 7 AF XY: 0.00204 AC XY: 277 AN XY: 135868

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00122 AC: 1788 AN: 1461876 Hom.: 34 Cov.: 32 AF XY: 0.00104 AC XY: 758 AN XY: 727238

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.0110 AC: 1669 AN: 152266 Hom.: 29 Cov.: 32 AF XY: 0.00998 AC XY: 743 AN XY: 74460

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00198 Hom.: 9

Bravo AF: 0.0131

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00331 AC: 402

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

McKusick-Kaufman syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2020

- -

Bardet-Biedl syndrome 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.5
Dann	Benign	0.91
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.096
Sift	Benign	0.24	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0010	B;B
Vest4		0.025
MVP		0.66
MPC		0.098
ClinPred		0.0013	T
GERP RS		1.8
Varity_R		0.022
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61734546; hg19: chr20-10386146;