20-10404812-C-T

Variant names:

• chr20-10404812-C-T
• rs6108549
• NM_170784.3:c.*435G>A

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.*435G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 154,656 control chromosomes in the GnomAD database, including 1,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1783 hom., cov: 32)
  • Exomes 𝑓: 0.13 (24 hom.)
• Consequence: MKKS NM_170784.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.632
• Publications: 2 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 (BayesDel_noAF=-0.86).
• BP6: Variant 20-10404812-C-T is Benign according to our data. Variant chr20-10404812-C-T is described in ClinVar as Benign. ClinVar VariationId is 337685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 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.*435G>A		3_prime_UTR	Exon 6 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.*435G>A		3_prime_UTR	Exon 6 of 6	NP_061336.1	Q9NPJ1
	MKKS	NR_072977.2		n.1509G>A		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.*435G>A		3_prime_UTR	Exon 6 of 6	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000651692.1		c.*435G>A		3_prime_UTR	Exon 7 of 7	ENSP00000498849.1	Q9NPJ1
	MKKS	ENST00000652676.1		n.*123G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21966 AN: 151924 Hom.: 1778 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.126 AC: 329 AN: 2614 Hom.: 24 Cov.: 0 AF XY: 0.128 AC XY: 184 AN XY: 1442

African (AFR) AF: 0.0556 AC: 1 AN: 18

American (AMR) AF: 0.148 AC: 72 AN: 488

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1 AN: 18

East Asian (EAS) AF: 0.242 AC: 16 AN: 66

South Asian (SAS) AF: 0.237 AC: 57 AN: 240

European-Finnish (FIN) AF: 0.0882 AC: 3 AN: 34

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.103 AC: 171 AN: 1668

Other (OTH) AF: 0.100 AC: 8 AN: 80

GnomAD4 genome AF: 0.145 AC: 21995 AN: 152042 Hom.: 1783 Cov.: 32 AF XY: 0.150 AC XY: 11179 AN XY: 74330

African (AFR) AF: 0.194 AC: 8064 AN: 41474

American (AMR) AF: 0.151 AC: 2300 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3466

East Asian (EAS) AF: 0.242 AC: 1250 AN: 5174

South Asian (SAS) AF: 0.234 AC: 1126 AN: 4804

European-Finnish (FIN) AF: 0.119 AC: 1251 AN: 10550

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

European-Non Finnish (NFE) AF: 0.107 AC: 7307 AN: 67996

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

Alfa AF: 0.129 Hom.: 175

Bravo AF: 0.145

Asia WGS AF: 0.213 AC: 741 AN: 3478

ClinVar

ClinVar submissions

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	-0.86
CADD	Benign	2.1
DANN	Benign	0.36
PhyloP100		-0.63
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: rs6108549; hg19: chr20-10385460;