rs79940214

Variant names:

• chr20-10405209-T-C
• rs79940214
• NM_170784.3:c.*38A>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.*38A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 1,526,246 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (117 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (107 hom.)
• Consequence: MKKS NM_170784.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.221
• Publications: 2 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 (BayesDel_noAF=-0.82).
• BP6: Variant 20-10405209-T-C is Benign according to our data. Variant chr20-10405209-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 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.*38A>G		3_prime_UTR	Exon 6 of 6	NP_740754.1	Q9NPJ1
	MKKS	NM_018848.3		c.*38A>G		3_prime_UTR	Exon 6 of 6	NP_061336.1	Q9NPJ1
	MKKS	NR_072977.2		n.1112A>G		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.*38A>G		3_prime_UTR	Exon 6 of 6	ENSP00000246062.4	Q9NPJ1
	MKKS	ENST00000399054.6	TSL:1	c.*38A>G		3_prime_UTR	Exon 6 of 6	ENSP00000382008.2	Q9NPJ1
	MKKS	ENST00000651692.1		c.*38A>G		3_prime_UTR	Exon 7 of 7	ENSP00000498849.1	Q9NPJ1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3437 AN: 152132 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00568 AC: 1064 AN: 187472 AF XY: 0.00435

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00285

GnomAD4 exome AF: 0.00213 AC: 2930 AN: 1373996 Hom.: 107 Cov.: 24 AF XY: 0.00183 AC XY: 1251 AN XY: 682828

African (AFR) AF: 0.0798 AC: 2481 AN: 31086

American (AMR) AF: 0.00455 AC: 171 AN: 37546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24586

East Asian (EAS) AF: 0.00 AC: 0 AN: 37798

South Asian (SAS) AF: 0.0000764 AC: 6 AN: 78492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50898

Middle Eastern (MID) AF: 0.00166 AC: 9 AN: 5428

European-Non Finnish (NFE) AF: 0.0000314 AC: 33 AN: 1051044

Other (OTH) AF: 0.00403 AC: 230 AN: 57118

GnomAD4 genome AF: 0.0226 AC: 3436 AN: 152250 Hom.: 117 Cov.: 32 AF XY: 0.0217 AC XY: 1616 AN XY: 74438

African (AFR) AF: 0.0778 AC: 3234 AN: 41552

American (AMR) AF: 0.0103 AC: 158 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68004

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00978 Hom.: 21

Bravo AF: 0.0262

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome 6 (1)
-	-	1	McKusick-Kaufman syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.67
PhyloP100		-0.22
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: rs79940214; hg19: chr20-10385857;