Genetic Variant RAB28:p.Gln189Lys (chr4-13376553-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001017979.3(RAB28):c.565C>A(p.Gln189Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q189Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RAB28
NM_001017979.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.02

Publications

3 publications found

Variant links:

Genes affected

RAB28 (HGNC:9768): (RAB28, member RAS oncogene family) This gene encodes a member of the Rab subfamily of Ras-related small GTPases. The encoded protein may be involved in regulating intracellular trafficking. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 9 and X. [provided by RefSeq, Apr 2009]

RAB28 Gene-Disease associations (from GenCC):

cone-rod dystrophy 18
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
RAB28-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RAB28 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.37718 (below the threshold of 3.09). Trascript score misZ: -0.0076161 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy, cone-rod dystrophy 18, RAB28-related retinopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017979.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAB28	NM_001017979.3	MANE Select	c.565C>A	p.Gln189Lys	missense	Exon 6 of 7	NP_001017979.1
RAB28	NM_004249.4	MANE Plus Clinical	c.565C>A	p.Gln189Lys	missense	Exon 6 of 8	NP_004240.2
RAB28	NM_001159601.2		c.565C>A	p.Gln189Lys	missense	Exon 6 of 8	NP_001153073.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAB28	ENST00000330852.10	TSL:1 MANE Select	c.565C>A	p.Gln189Lys	missense	Exon 6 of 7	ENSP00000328551.5
RAB28	ENST00000288723.9	TSL:1 MANE Plus Clinical	c.565C>A	p.Gln189Lys	missense	Exon 6 of 8	ENSP00000288723.4
RAB28	ENST00000508274.5	TSL:1	n.*147C>A		non_coding_transcript_exon	Exon 5 of 6	ENSP00000424043.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.047

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

PhyloP100

9.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.38

Sift

Benign

0.59

Sift4G

Benign

0.90

Polyphen

0.33

Vest4

0.68

MutPred

0.37

Gain of ubiquitination at Q189 (P = 0.0162)

MVP

0.85

MPC

0.28

ClinPred

0.77

GERP RS

4.9

Varity_R

0.28

gMVP

0.58

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over