20-10404855-A-G

Position:

• chr20-10404855-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000347364.7(MKKS):​c.*392T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 162,214 control chromosomes in the GnomAD database, including 1,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1781 hom., cov: 32)
  • Exomes 𝑓: 0.12 (85 hom.)
• Consequence: MKKS ENST00000347364.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.346

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-10404855-A-G is Benign according to our data. Variant chr20-10404855-A-G is described in ClinVar as [Benign]. Clinvar id is 337686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3	c.*392T>C		3_prime_UTR_variant	6/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.*392T>C		3_prime_UTR_variant	6/6		NP_061336.1
MKKS	NR_072977.2	n.1466T>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.*392T>C		3_prime_UTR_variant	6/6	1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000651692.1	c.*392T>C		3_prime_UTR_variant	7/7			ENSP00000498849	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21967 AN: 152050 Hom.: 1776 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.119 AC: 1199 AN: 10046 Hom.: 85 Cov.: 0 AF XY: 0.128 AC XY: 693 AN XY: 5420

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.0820

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0965

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.145 AC: 21996 AN: 152168 Hom.: 1781 Cov.: 32 AF XY: 0.150 AC XY: 11184 AN XY: 74394

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.133

Alfa AF: 0.127 Hom.: 172

Bravo AF: 0.145

Asia WGS AF: 0.213 AC: 741 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

McKusick-Kaufman syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Bardet-Biedl syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs2294901; hg19: chr20-10385503;