20-10432111-A-T

Variant names:

• chr20-10432111-A-T
• rs6108572
• NM_170784.3:c.-649+1997T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170784.3(MKKS):​c.-649+1997T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 152,032 control chromosomes in the GnomAD database, including 21,159 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (21159 hom., cov: 32)
• Consequence: MKKS NM_170784.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208
• Publications: 11 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):

ENSG00000285508 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 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.-649+1997T>A		intron	N/A	NP_740754.1
	LOC128706665	NM_001394148.2	MANE Select	c.-22+1997T>A		intron	N/A	NP_001381077.1
	LOC128706666	NM_001394149.2	MANE Select	c.-276+1997T>A		intron	N/A	NP_001381078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-649+1997T>A		intron	N/A	ENSP00000246062.4
	ENSG00000285723	ENST00000649912.2	MANE Select	c.-22+1997T>A		intron	N/A	ENSP00000497510.1
	ENSG00000285508	ENST00000713549.1	MANE Select	c.-276+1997T>A		intron	N/A	ENSP00000518845.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78420 AN: 151914 Hom.: 21158 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.516 AC: 78439 AN: 152032 Hom.: 21159 Cov.: 32 AF XY: 0.517 AC XY: 38449 AN XY: 74314

African (AFR) AF: 0.386 AC: 15991 AN: 41470

American (AMR) AF: 0.508 AC: 7771 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1701 AN: 3470

East Asian (EAS) AF: 0.238 AC: 1227 AN: 5156

South Asian (SAS) AF: 0.529 AC: 2547 AN: 4818

European-Finnish (FIN) AF: 0.647 AC: 6840 AN: 10572

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40675 AN: 67946

Other (OTH) AF: 0.488 AC: 1029 AN: 2108

Alfa AF: 0.561 Hom.: 3037

Bravo AF: 0.495

Asia WGS AF: 0.356 AC: 1238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.73
PhyloP100		0.21
PromoterAI		-0.059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6108572; hg19: chr20-10412759;