NM_006267.5:c.2173A>G

Variant names:

• chr2-108753942-A-G
• rs17414315
• NM_006267.5:c.2173A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):​c.2173A>G​(p.Ser725Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,611,980 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S725N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (23 hom., cov: 31)
  • Exomes 𝑓: 0.00085 (9 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.09
• Publications: 2 publications found

Genes affected

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049237907).
• BP6: Variant 2-108753942-A-G is Benign according to our data. Variant chr2-108753942-A-G is described in ClinVar as Benign. ClinVar VariationId is 382437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1331/152336) while in subpopulation AFR AF = 0.0293 (1219/41568). AF 95% confidence interval is 0.028. There are 23 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1331 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006267.5. 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
	RANBP2	NM_006267.5	MANE Select	c.2173A>G	p.Ser725Gly	missense	Exon 15 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2173A>G	p.Ser725Gly	missense	Exon 15 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2173A>G	p.Ser725Gly	missense	Exon 15 of 29	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.2173A>G	p.Ser725Gly	missense	Exon 15 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2170A>G	p.Ser724Gly	missense	Exon 15 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2173A>G	p.Ser725Gly	missense	Exon 15 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00867 AC: 1319 AN: 152218 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00218 AC: 543 AN: 249538 AF XY: 0.00160

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000854 AC: 1247 AN: 1459644 Hom.: 9 Cov.: 34 AF XY: 0.000756 AC XY: 549 AN XY: 726124

African (AFR) AF: 0.0285 AC: 951 AN: 33406

American (AMR) AF: 0.00192 AC: 86 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39674

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4134

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111808

Other (OTH) AF: 0.00223 AC: 134 AN: 60202

GnomAD4 genome AF: 0.00874 AC: 1331 AN: 152336 Hom.: 23 Cov.: 31 AF XY: 0.00846 AC XY: 630 AN XY: 74490

African (AFR) AF: 0.0293 AC: 1219 AN: 41568

American (AMR) AF: 0.00568 AC: 87 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00241 Hom.: 0

Bravo AF: 0.0102

ESP6500AA AF: 0.0237 AC: 103

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00265 AC: 321

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.059
Sift	Benign	0.26	T
Sift4G	Uncertain	0.046	D
Polyphen		0.36	B
Vest4		0.29
MVP		0.45
MPC		0.96
ClinPred		0.019	T
GERP RS		2.6
Varity_R		0.056
gMVP		0.41
Mutation Taster		=95/5	polymorphism

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: rs17414315; hg19: chr2-109370398;