chr20-10405411-G-A

Variant names:

• chr20-10405411-G-A
• rs1547
• NM_170784.3:c.1549C>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.1549C>T​(p.Arg517Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,998 control chromosomes in the GnomAD database, including 14,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R517H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1803 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12666 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0360
• Publications: 44 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 (MetaRNN=0.0049877167).
• BP6: Variant 20-10405411-G-A is Benign according to our data. Variant chr20-10405411-G-A is described in ClinVar as Benign. ClinVar VariationId is 95922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 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.1549C>T	p.Arg517Cys	missense	Exon 6 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.1549C>T	p.Arg517Cys	missense	Exon 6 of 6	NP_061336.1	Q9NPJ1
	MKKS	NR_072977.2		n.910C>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.1549C>T	p.Arg517Cys	missense	Exon 6 of 6	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000399054.6	TSL:1	c.1549C>T	p.Arg517Cys	missense	Exon 6 of 6	ENSP00000382008.2	Q9NPJ1
	MKKS	ENST00000651692.1		c.1549C>T	p.Arg517Cys	missense	Exon 7 of 7	ENSP00000498849.1	Q9NPJ1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22034 AN: 152046 Hom.: 1798 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.141 AC: 35430 AN: 251398 AF XY: 0.144

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0999

Gnomad EAS exome AF: 0.242

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.124 AC: 181988 AN: 1461832 Hom.: 12666 Cov.: 32 AF XY: 0.127 AC XY: 92487 AN XY: 727220

African (AFR) AF: 0.197 AC: 6596 AN: 33472

American (AMR) AF: 0.109 AC: 4877 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2652 AN: 26134

East Asian (EAS) AF: 0.250 AC: 9935 AN: 39696

South Asian (SAS) AF: 0.240 AC: 20704 AN: 86258

European-Finnish (FIN) AF: 0.116 AC: 6175 AN: 53418

Middle Eastern (MID) AF: 0.136 AC: 784 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122141 AN: 1111970

Other (OTH) AF: 0.135 AC: 8124 AN: 60392

GnomAD4 genome AF: 0.145 AC: 22063 AN: 152166 Hom.: 1803 Cov.: 32 AF XY: 0.151 AC XY: 11217 AN XY: 74416

African (AFR) AF: 0.195 AC: 8074 AN: 41490

American (AMR) AF: 0.151 AC: 2307 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3470

East Asian (EAS) AF: 0.250 AC: 1294 AN: 5174

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4822

European-Finnish (FIN) AF: 0.118 AC: 1254 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7304 AN: 68004

Other (OTH) AF: 0.134 AC: 283 AN: 2114

Alfa AF: 0.121 Hom.: 4450

Bravo AF: 0.145

TwinsUK AF: 0.115 AC: 427

ALSPAC AF: 0.125 AC: 483

ESP6500AA AF: 0.172 AC: 757

ESP6500EA AF: 0.112 AC: 962

ExAC AF: 0.144 AC: 17483

Asia WGS AF: 0.218 AC: 756 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome 6 (1)
-	-	1	Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome (1)
-	-	1	McKusick-Kaufman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.7
DANN	Benign	0.82
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N
PhyloP100		0.036
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.18
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.14
ClinPred		0.00063	T
GERP RS		-2.8
Varity_R		0.051
gMVP		0.41
Mutation Taster		=94/6	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: rs1547; hg19: chr20-10386059; COSMIC: COSV61398017;