NM_170784.3:c.1669A>G

Variant names:

• chr20-10405291-T-C
• NM_170784.3:c.1669A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170784.3(MKKS):​c.1669A>G​(p.Asn557Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKKS	NM_170784.3	c.1669A>G	p.Asn557Asp	missense_variant	Exon 6 of 6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.1669A>G	p.Asn557Asp	missense_variant	Exon 6 of 6		NP_061336.1
MKKS	NR_072977.2	n.1030A>G		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.1669A>G	p.Asn557Asp	missense_variant	Exon 6 of 6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.1669A>G	p.Asn557Asp	missense_variant	Exon 6 of 6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.1669A>G	p.Asn557Asp	missense_variant	Exon 7 of 7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.1313A>G		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461088 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.15	T;T
Sift4G	Benign	0.069	T;T
Polyphen		0.35	B;B
Vest4		0.54
MutPred		0.71		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.87
MPC		0.30
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.20
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-10385939;