chr2-108753853-A-C

Variant names:

• chr2-108753853-A-C
• rs148298842
• NM_006267.5:c.2084A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006267.5(RANBP2):​c.2084A>C​(p.Glu695Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000767 in 1,611,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.26
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07865384).
• BP6: Variant 2-108753853-A-C is Benign according to our data. Variant chr2-108753853-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469435.
• BS2: High AC in GnomAd4 at 85 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.2084A>C	p.Glu695Ala	missense	Exon 15 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2084A>C	p.Glu695Ala	missense	Exon 15 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2084A>C	p.Glu695Ala	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.2084A>C	p.Glu695Ala	missense	Exon 15 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2081A>C	p.Glu694Ala	missense	Exon 15 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2084A>C	p.Glu695Ala	missense	Exon 15 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000284 AC: 71 AN: 250132 AF XY: 0.000280

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000789 AC: 1151 AN: 1459612 Hom.: 0 Cov.: 34 AF XY: 0.000755 AC XY: 548 AN XY: 726108

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

African (AFR) AF: 0.000210 AC: 7 AN: 33406

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39682

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86162

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000959 AC: 1066 AN: 1111758

Other (OTH) AF: 0.000615 AC: 37 AN: 60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 41 AN XY: 74378

African (AFR) AF: 0.000241 AC: 10 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000495

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.00120

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.021
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.086
Sift	Benign	0.24	T
Sift4G	Uncertain	0.021	D
Polyphen		0.43	B
Vest4		0.25
MVP		0.36
MPC		1.1
ClinPred		0.032	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.32
Mutation Taster		=82/18	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: rs148298842; hg19: chr2-109370309; COSMIC: COSV51701771; COSMIC: COSV51701771;