chr20-10434132-C-CCAGGCCGCCA

Variant names:

• chr20-10434132-C-CCAGGCCGCCA
• rs16996729
• NM_170784.3:c.-683_-674dupTGGCGGCCTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_170784.3(MKKS):​c.-683_-674dupTGGCGGCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 152,674 control chromosomes in the GnomAD database, including 325 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.061 (325 hom., cov: 32)
  • Exomes 𝑓: 0.030 (0 hom.)
• Consequence: MKKS NM_170784.3 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.69
• 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: 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

LOC128706665 (HGNC:0):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 20-10434132-C-CCAGGCCGCCA is Benign according to our data. Variant chr20-10434132-C-CCAGGCCGCCA is described in ClinVar as Benign. ClinVar VariationId is 21667.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0802 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.-683_-674dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 6	NP_740754.1
	LOC128706665	NM_001394148.2	MANE Select	c.-56_-47dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	NP_001381077.1
	LOC128706666	NM_001394149.2	MANE Select	c.-310_-301dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	NP_001381078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-683_-674dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 6	ENSP00000246062.4
	ENSG00000285723	ENST00000649912.2	MANE Select	c.-56_-47dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	ENSP00000497510.1
	ENSG00000285508	ENST00000713549.1	MANE Select	c.-310_-301dupTGGCGGCCTG		5_prime_UTR	Exon 1 of 3	ENSP00000518845.1

Frequencies

GnomAD3 genomes AF: 0.0610 AC: 9281 AN: 152050 Hom.: 325 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0659

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0620

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.0296 AC: 15 AN: 506 Hom.: 0 Cov.: 0 AF XY: 0.0250 AC XY: 10 AN XY: 400

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.00 AC: 0 AN: 12

European-Finnish (FIN) AF: 0.0333 AC: 1 AN: 30

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0317 AC: 13 AN: 410

Other (OTH) AF: 0.00 AC: 0 AN: 18

GnomAD4 genome AF: 0.0610 AC: 9288 AN: 152168 Hom.: 325 Cov.: 32 AF XY: 0.0624 AC XY: 4641 AN XY: 74374

African (AFR) AF: 0.0533 AC: 2216 AN: 41544

American (AMR) AF: 0.0840 AC: 1284 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.0661 AC: 340 AN: 5146

South Asian (SAS) AF: 0.0502 AC: 242 AN: 4822

European-Finnish (FIN) AF: 0.0713 AC: 756 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0620 AC: 4216 AN: 67974

Other (OTH) AF: 0.0535 AC: 113 AN: 2114

Alfa AF: 0.0208 Hom.: 6

Asia WGS AF: 0.0580 AC: 200 AN: 3478

ClinVar

ClinVar submissions as Germline

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
PhyloP100		-2.7
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16996729; hg19: chr20-10414780;