rs1545

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-10405365-C-A
• chr20-10405365-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170784.3(MKKS):​c.1595G>T​(p.Gly532Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,980 control chromosomes in the GnomAD database, including 14,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1789 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12593 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006698847).
• BP6: Variant 20-10405365-C-A is Benign according to our data. Variant chr20-10405365-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 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.1595G>T	p.Gly532Val	missense	Exon 6 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.1595G>T	p.Gly532Val	missense	Exon 6 of 6	NP_061336.1	Q9NPJ1
	MKKS	NR_072977.2		n.956G>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.1595G>T	p.Gly532Val	missense	Exon 6 of 6	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000399054.6	TSL:1	c.1595G>T	p.Gly532Val	missense	Exon 6 of 6	ENSP00000382008.2	Q9NPJ1
	MKKS	ENST00000651692.1		c.1595G>T	p.Gly532Val	missense	Exon 7 of 7	ENSP00000498849.1	Q9NPJ1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21996 AN: 152052 Hom.: 1784 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.140 AC: 35257 AN: 251320 AF XY: 0.144

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0999

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.124 AC: 181734 AN: 1461808 Hom.: 12593 Cov.: 32 AF XY: 0.127 AC XY: 92366 AN XY: 727210

African (AFR) AF: 0.197 AC: 6596 AN: 33478

American (AMR) AF: 0.109 AC: 4870 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2652 AN: 26134

East Asian (EAS) AF: 0.245 AC: 9713 AN: 39700

South Asian (SAS) AF: 0.240 AC: 20705 AN: 86252

European-Finnish (FIN) AF: 0.116 AC: 6175 AN: 53414

Middle Eastern (MID) AF: 0.136 AC: 784 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122143 AN: 1111956

Other (OTH) AF: 0.134 AC: 8096 AN: 60390

GnomAD4 genome AF: 0.145 AC: 22025 AN: 152172 Hom.: 1789 Cov.: 32 AF XY: 0.150 AC XY: 11195 AN XY: 74394

African (AFR) AF: 0.195 AC: 8078 AN: 41524

American (AMR) AF: 0.151 AC: 2302 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3472

East Asian (EAS) AF: 0.241 AC: 1248 AN: 5168

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4810

European-Finnish (FIN) AF: 0.119 AC: 1256 AN: 10592

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7313 AN: 68008

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.122 Hom.: 4167

Bravo AF: 0.145

TwinsUK AF: 0.115 AC: 427

ALSPAC AF: 0.125 AC: 480

ESP6500AA AF: 0.172 AC: 757

ESP6500EA AF: 0.112 AC: 962

ExAC AF: 0.143 AC: 17419

Asia WGS AF: 0.214 AC: 743 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome 6 (1)
-	-	1	Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome (1)
-	-	1	McKusick-Kaufman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.22
DANN	Benign	0.88
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.17
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.15	T
Sift4G	Benign	0.22	T
Polyphen		0.14	B
Vest4		0.058
MPC		0.18
ClinPred		0.0017	T
GERP RS		-1.6
Varity_R		0.035
gMVP		0.54
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: rs1545; hg19: chr20-10386013; COSMIC: COSV61398010;