chr20-10412514-A-C

Variant names:

• chr20-10412514-A-C
• rs6133917
• NM_170784.3:c.985+16T>G

Variant summary

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

The NM_018848.3(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_018848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0780
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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=-0.62).
• BP6: Variant 20-10412514-A-C is Benign according to our data. Variant chr20-10412514-A-C is described in ClinVar as Benign. ClinVar VariationId is 196492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	NM_170784.3	MANE Select	c.985+16T>G		intron	N/A	NP_740754.1
	MKKS	NM_018848.3		c.985+16T>G		intron	N/A	NP_061336.1
	MKKS	NR_072977.2		n.347-3711T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.985+16T>G		intron	N/A	ENSP00000246062.4
	MKKS	ENST00000399054.6	TSL:1	c.985+16T>G		intron	N/A	ENSP00000382008.2
	MKKS	ENST00000651692.1		c.985+16T>G		intron	N/A	ENSP00000498849.1

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

GnomAD2 exomes AF: 0.140 AC: 35060 AN: 249660 AF XY: 0.144

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 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

African (AFR) AF: 0.195 AC: 6509 AN: 33444

American (AMR) AF: 0.109 AC: 4866 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2652 AN: 26130

East Asian (EAS) AF: 0.245 AC: 9707 AN: 39682

South Asian (SAS) AF: 0.240 AC: 20718 AN: 86204

European-Finnish (FIN) AF: 0.116 AC: 5995 AN: 51898

Middle Eastern (MID) AF: 0.135 AC: 778 AN: 5762

European-Non Finnish (NFE) AF: 0.110 AC: 121840 AN: 1111062

Other (OTH) AF: 0.134 AC: 8074 AN: 60348

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

African (AFR) AF: 0.193 AC: 7998 AN: 41528

American (AMR) AF: 0.151 AC: 2302 AN: 15294

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

East Asian (EAS) AF: 0.242 AC: 1253 AN: 5178

South Asian (SAS) AF: 0.235 AC: 1136 AN: 4826

European-Finnish (FIN) AF: 0.118 AC: 1255 AN: 10604

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

European-Non Finnish (NFE) AF: 0.107 AC: 7304 AN: 67998

Other (OTH) AF: 0.133 AC: 280 AN: 2110

Alfa AF: 0.103 Hom.: 395

Bravo AF: 0.144

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.5
DANN	Benign	0.86
PhyloP100		-0.078
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6133917; hg19: chr20-10393162; COSMIC: COSV61398022; COSMIC: COSV61398022;