2-108729208-A-T

Variant names:

• chr2-108729208-A-T
• rs755428275
• NM_006267.5:c.140+9A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_006267.5(RANBP2):​c.140+9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,565,694 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (1 hom.)
• Consequence: RANBP2 NM_006267.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.114
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-108729208-A-T is Benign according to our data. Variant chr2-108729208-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1102715.Status of the report is criteria_provided_single_submitter, 1 stars.

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.140+9A>T		intron	N/A	NP_006258.3
	RANBP2	NM_001415871.1		c.140+9A>T		intron	N/A	NP_001402800.1
	RANBP2	NM_001415873.1		c.140+9A>T		intron	N/A	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.140+9A>T		intron	N/A	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.137+9A>T		intron	N/A	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.140+9A>T		intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000926 AC: 2 AN: 215946 AF XY: 0.00

Gnomad AFR exome AF: 0.000148

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000149 AC: 21 AN: 1413466 Hom.: 1 Cov.: 31 AF XY: 0.0000142 AC XY: 10 AN XY: 702854

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

African (AFR) AF: 0.000339 AC: 11 AN: 32478

American (AMR) AF: 0.00 AC: 0 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.00 AC: 0 AN: 83470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090088

Other (OTH) AF: 0.000171 AC: 10 AN: 58642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000763141), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		-0.11

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: rs755428275; hg19: chr2-109345664;