20-10405365-C-G

Variant names:

• chr20-10405365-C-G
• rs1545
• NM_170784.3:c.1595G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170784.3(MKKS):​c.1595G>C​(p.Gly532Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G532V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 47 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19633746).

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.1595G>C	p.Gly532Ala	missense	Exon 6 of 6	NP_740754.1
	MKKS	NM_018848.3		c.1595G>C	p.Gly532Ala	missense	Exon 6 of 6	NP_061336.1
	MKKS	NR_072977.2		n.956G>C		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.1595G>C	p.Gly532Ala	missense	Exon 6 of 6	ENSP00000246062.4
	MKKS	ENST00000399054.6	TSL:1	c.1595G>C	p.Gly532Ala	missense	Exon 6 of 6	ENSP00000382008.2
	MKKS	ENST00000651692.1		c.1595G>C	p.Gly532Ala	missense	Exon 7 of 7	ENSP00000498849.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.057
DANN	Benign	0.72
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.17
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.18
Sift	Benign	0.39	T
Sift4G	Benign	0.94	T
Polyphen		0.28	B
Vest4		0.10
MutPred		0.42		Gain of helix (P = 0.132)
MVP		0.92
MPC		0.12
ClinPred		0.11	T
GERP RS		-1.6
Varity_R		0.021
gMVP		0.46
Mutation Taster		=98/2	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: rs1545; hg19: chr20-10386013;