NM_170784.3:c.-74G>A

Variant names:

• chr20-10413588-C-T
• rs113994194
• NM_170784.3:c.-74G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_170784.3(MKKS):​c.-74G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,486,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MKKS NM_170784.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.500
• 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

ENSG00000285508 (HGNC:):

LOC128706665 (HGNC:0):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-10413588-C-T is Benign according to our data. Variant chr20-10413588-C-T is described in ClinVar as Benign. ClinVar VariationId is 21668.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_170784.3	MANE Select	c.-74G>A		5_prime_UTR	Exon 3 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_061336.1	Q9NPJ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000399054.6	TSL:1	c.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000382008.2	Q9NPJ1
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-74G>A		5_prime_UTR	Exon 3 of 6	ENSP00000246062.4	Q9NPJ1

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000159 AC: 212 AN: 1333804 Hom.: 0 Cov.: 20 AF XY: 0.000152 AC XY: 102 AN XY: 670348

African (AFR) AF: 0.00259 AC: 79 AN: 30492

American (AMR) AF: 0.000343 AC: 15 AN: 43712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.000205 AC: 8 AN: 39052

South Asian (SAS) AF: 0.000290 AC: 24 AN: 82768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50644

Middle Eastern (MID) AF: 0.000887 AC: 4 AN: 4512

European-Non Finnish (NFE) AF: 0.0000569 AC: 57 AN: 1001366

Other (OTH) AF: 0.000446 AC: 25 AN: 56034

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74430

African (AFR) AF: 0.00260 AC: 108 AN: 41534

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.53
PhyloP100		0.50
Mutation Taster		=299/1	polymorphism

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: rs113994194; hg19: chr20-10394236;