2-109548083-A-C

Variant names:

• chr2-109548083-A-C
• rs10496431
• NM_144710.5:c.1162-1846T>G

Variant summary

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

The NM_144710.5(SEPTIN10):​c.1162-1846T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 152,176 control chromosomes in the GnomAD database, including 749 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 0.064 (749 hom., cov: 31)
• Consequence: SEPTIN10 NM_144710.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321
• Publications: 3 publications found

Genes affected

SEPTIN10 (HGNC:14349): (septin 10) This gene encodes a member of the septin family of cytoskeletal proteins with GTPase activity. This protein localizes to the cytoplasm and nucleus and displays GTP-binding and GTPase activity. A pseudogene for this gene is located on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

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, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN10	NM_144710.5	c.1162-1846T>G		intron_variant	Intron 9 of 10	ENST00000397712.7	NP_653311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN10	ENST00000397712.7	c.1162-1846T>G		intron_variant	Intron 9 of 10	1	NM_144710.5	ENSP00000380824.2

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9760 AN: 152060 Hom.: 739 Cov.: 31

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.0534

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0688

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0643 AC: 9786 AN: 152176 Hom.: 749 Cov.: 31 AF XY: 0.0689 AC XY: 5128 AN XY: 74402

African (AFR) AF: 0.0505 AC: 2097 AN: 41538

American (AMR) AF: 0.205 AC: 3131 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0534 AC: 185 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1236 AN: 5150

South Asian (SAS) AF: 0.0842 AC: 405 AN: 4812

European-Finnish (FIN) AF: 0.0533 AC: 564 AN: 10588

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1979 AN: 68020

Other (OTH) AF: 0.0676 AC: 143 AN: 2116

Alfa AF: 0.0639 Hom.: 470

Bravo AF: 0.0813

Asia WGS AF: 0.149 AC: 517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.2
DANN	Benign	0.74
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs10496431; hg19: chr2-110305660;