20-10430806-A-T

Variant names:

• chr20-10430806-A-T
• rs6077785
• NM_170784.3:c.-649+3302T>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+3302T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 152,082 control chromosomes in the GnomAD database, including 18,997 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 0.49 (18997 hom., cov: 33)
• Consequence: MKKS NM_170784.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.432
• 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: 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

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.552 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.-649+3302T>A		intron	N/A	NP_740754.1	Q9NPJ1
	LOC128706665	NM_001394148.2	MANE Select	c.-22+3302T>A		intron	N/A	NP_001381077.1
	LOC128706666	NM_001394149.2	MANE Select	c.-276+3302T>A		intron	N/A	NP_001381078.1	V9GZ13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.-649+3302T>A		intron	N/A	ENSP00000246062.4	Q9NPJ1
	ENSG00000285723	ENST00000649912.2	MANE Select	c.-22+3302T>A		intron	N/A	ENSP00000497510.1	Q9HB66
	ENSG00000285508	ENST00000713549.1	MANE Select	c.-276+3302T>A		intron	N/A	ENSP00000518845.1	V9GZ13

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74725 AN: 151964 Hom.: 18995 Cov.: 33

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.492 AC: 74752 AN: 152082 Hom.: 18997 Cov.: 33 AF XY: 0.495 AC XY: 36788 AN XY: 74352

African (AFR) AF: 0.384 AC: 15917 AN: 41462

American (AMR) AF: 0.502 AC: 7666 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1615 AN: 3472

East Asian (EAS) AF: 0.250 AC: 1294 AN: 5180

South Asian (SAS) AF: 0.493 AC: 2377 AN: 4818

European-Finnish (FIN) AF: 0.607 AC: 6411 AN: 10570

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37866 AN: 67992

Other (OTH) AF: 0.472 AC: 996 AN: 2112

Alfa AF: 0.408 Hom.: 1192

Bravo AF: 0.477

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		-0.43
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: rs6077785; hg19: chr20-10411454;