rs2287691

Variant names:

• chr19-40780258-C-G
• rs2287691
• NM_016154.5:c.98-127C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016154.5(RAB4B):​c.98-127C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,434,084 control chromosomes in the GnomAD database, including 21,204 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3419 hom., cov: 31)
  • Exomes 𝑓: 0.16 (17785 hom.)
• Consequence: RAB4B NM_016154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• Publications: 3 publications found

Genes affected

RAB4B (HGNC:9782): (RAB4B, member RAS oncogene family) Predicted to enable G protein activity and GTP binding activity. Involved in glucose import. Located in insulin-responsive compartment; perinuclear region of cytoplasm; and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB4B-EGLN2 (HGNC:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

MIA-RAB4B (HGNC:48352): (MIA-RAB4B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MIA (melanoma inhibitory activity) and RAB4B (RAB4B, member RAS oncogene family) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ENSG00000282951 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016154.5. 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
	RAB4B	NM_016154.5	MANE Select	c.98-127C>G		intron	N/A	NP_057238.3
	MIA-RAB4B	NR_037775.1		n.460-127C>G		intron	N/A
	RAB4B-EGLN2	NR_037791.1		n.255-127C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB4B	ENST00000357052.8	TSL:1 MANE Select	c.98-127C>G		intron	N/A	ENSP00000349560.2	P61018-1
	RAB4B	ENST00000378307.9	TSL:1	n.98-127C>G		intron	N/A	ENSP00000367557.4	F6SQB9
	RAB4B-EGLN2	ENST00000594136.2	TSL:2	n.98-127C>G		intron	N/A	ENSP00000469872.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30262 AN: 151840 Hom.: 3415 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.194

GnomAD4 exome AF: 0.163 AC: 208720 AN: 1282128 Hom.: 17785 Cov.: 23 AF XY: 0.163 AC XY: 102799 AN XY: 629008

African (AFR) AF: 0.316 AC: 9022 AN: 28508

American (AMR) AF: 0.183 AC: 4889 AN: 26650

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2721 AN: 20138

East Asian (EAS) AF: 0.125 AC: 4445 AN: 35604

South Asian (SAS) AF: 0.205 AC: 13780 AN: 67314

European-Finnish (FIN) AF: 0.148 AC: 6965 AN: 47092

Middle Eastern (MID) AF: 0.164 AC: 862 AN: 5260

European-Non Finnish (NFE) AF: 0.157 AC: 157158 AN: 997936

Other (OTH) AF: 0.166 AC: 8878 AN: 53626

GnomAD4 genome AF: 0.199 AC: 30285 AN: 151956 Hom.: 3419 Cov.: 31 AF XY: 0.197 AC XY: 14614 AN XY: 74284

African (AFR) AF: 0.315 AC: 13038 AN: 41380

American (AMR) AF: 0.181 AC: 2762 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3472

East Asian (EAS) AF: 0.0787 AC: 406 AN: 5156

South Asian (SAS) AF: 0.196 AC: 946 AN: 4822

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10584

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10652 AN: 67968

Other (OTH) AF: 0.192 AC: 404 AN: 2108

Alfa AF: 0.199 Hom.: 394

Bravo AF: 0.205

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.84
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2287691;

hg19: chr19-41286163;

COSMIC: COSV54571056;

COSMIC: COSV54571056;