rs2294901

Variant names:

• chr20-10404855-A-G
• rs2294901
• NM_170784.3:c.*392T>C

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.*392T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 162,214 control chromosomes in the GnomAD database, including 1,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1781 hom., cov: 32)
  • Exomes 𝑓: 0.12 (85 hom.)
• Consequence: MKKS NM_170784.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.346
• Publications: 3 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=-0.82).
• BP6: Variant 20-10404855-A-G is Benign according to our data. Variant chr20-10404855-A-G is described in ClinVar as Benign. ClinVar VariationId is 337686.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_170784.3. 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.*392T>C		3_prime_UTR	Exon 6 of 6	NP_740754.1
	MKKS	NR_072977.2		n.1466T>C		non_coding_transcript_exon	Exon 5 of 5
	MKKS	NM_018848.3		c.*392T>C		3_prime_UTR	Exon 6 of 6	NP_061336.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.*392T>C		3_prime_UTR	Exon 6 of 6	ENSP00000246062.4
	MKKS	ENST00000651692.1		c.*392T>C		3_prime_UTR	Exon 7 of 7	ENSP00000498849.1
	MKKS	ENST00000652676.1		n.*80T>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21967 AN: 152050 Hom.: 1776 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: 0.242

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

GnomAD4 exome AF: 0.119 AC: 1199 AN: 10046 Hom.: 85 Cov.: 0 AF XY: 0.128 AC XY: 693 AN XY: 5420

African (AFR) AF: 0.107 AC: 6 AN: 56

American (AMR) AF: 0.110 AC: 195 AN: 1780

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 10 AN: 122

East Asian (EAS) AF: 0.218 AC: 89 AN: 408

South Asian (SAS) AF: 0.214 AC: 267 AN: 1246

European-Finnish (FIN) AF: 0.110 AC: 23 AN: 210

Middle Eastern (MID) AF: 0.214 AC: 3 AN: 14

European-Non Finnish (NFE) AF: 0.0965 AC: 560 AN: 5804

Other (OTH) AF: 0.113 AC: 46 AN: 406

GnomAD4 genome AF: 0.145 AC: 21996 AN: 152168 Hom.: 1781 Cov.: 32 AF XY: 0.150 AC XY: 11184 AN XY: 74394

African (AFR) AF: 0.194 AC: 8054 AN: 41508

American (AMR) AF: 0.150 AC: 2299 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1251 AN: 5168

South Asian (SAS) AF: 0.235 AC: 1132 AN: 4822

European-Finnish (FIN) AF: 0.118 AC: 1254 AN: 10588

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

European-Non Finnish (NFE) AF: 0.107 AC: 7305 AN: 68012

Other (OTH) AF: 0.133 AC: 282 AN: 2114

Alfa AF: 0.152 Hom.: 450

Bravo AF: 0.145

Asia WGS AF: 0.213 AC: 741 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome 6 (1)
-	-	1	McKusick-Kaufman syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.77
PhyloP100		0.35
Mutation Taster		=100/0	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: rs2294901; hg19: chr20-10385503;