2-237578155-C-T

Variant names:

• chr2-237578155-C-T
• rs144305164
• NM_022449.4:c.158G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022449.4(RAB17):​c.158G>A​(p.Cys53Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RAB17 NM_022449.4 missense, splice_region
• Scores: Splicing: ADA: 0.04286
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

Genes affected

RAB17 (HGNC:16523): (RAB17, member RAS oncogene family) The Rab subfamily of small GTPases plays an important role in the regulation of membrane trafficking. RAB17 is an epithelial cell-specific GTPase (Lutcke et al., 1993 [PubMed 8486736]).[supplied by OMIM, Oct 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022449.4. 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
	RAB17	NM_022449.4	MANE Select	c.158G>A	p.Cys53Tyr	missense splice_region	Exon 3 of 6	NP_071894.1	Q9H0T7-1
	RAB17	NR_033308.2		n.429-773G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB17	ENST00000264601.8	TSL:1 MANE Select	c.158G>A	p.Cys53Tyr	missense splice_region	Exon 3 of 6	ENSP00000264601.3	Q9H0T7-1
	RAB17	ENST00000477149.5	TSL:1	n.1416G>A		non_coding_transcript_exon	Exon 1 of 3
	RAB17	ENST00000392001.6	TSL:1	n.158-773G>A		intron	N/A	ENSP00000375858.2	F8WAG1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250070 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455802 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722994

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107216

Other (OTH) AF: 0.00 AC: 0 AN: 60070

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.70
MVP		0.70
MPC		0.56
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.88
gMVP		0.65
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.043
dbscSNV1_RF	Benign	0.22
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

Other links and lift over

dbSNP: rs144305164; hg19: chr2-238486798;