chr2-108874988-A-G

Variant names:

• chr2-108874988-A-G
• rs7591305
• NM_144978.3:c.1833-1100A>G

Variant summary

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

The NM_144978.3(CCDC138):​c.1833-1100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 151,504 control chromosomes in the GnomAD database, including 57,855 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 0.87 (57855 hom., cov: 29)
• Consequence: CCDC138 NM_144978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 5 publications found

Genes affected

CCDC138 (HGNC:26531): (coiled-coil domain containing 138)

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	NM_144978.3	MANE Select	c.1833-1100A>G		intron	N/A	NP_659415.1
	CCDC138	NM_001351544.2		c.1851-1100A>G		intron	N/A	NP_001338473.1
	CCDC138	NM_001351545.1		c.1818-1100A>G		intron	N/A	NP_001338474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	ENST00000295124.9	TSL:2 MANE Select	c.1833-1100A>G		intron	N/A	ENSP00000295124.4
	CCDC138	ENST00000412964.6	TSL:1	c.1694-1100A>G		intron	N/A	ENSP00000411800.2
	CCDC138	ENST00000608781.1	TSL:3	c.44-7683A>G		intron	N/A	ENSP00000477316.1

Frequencies

GnomAD3 genomes AF: 0.871 AC: 131860 AN: 151388 Hom.: 57822 Cov.: 29

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.890

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

GnomAD4 genome AF: 0.871 AC: 131946 AN: 151504 Hom.: 57855 Cov.: 29 AF XY: 0.873 AC XY: 64624 AN XY: 74004

African (AFR) AF: 0.763 AC: 31530 AN: 41346

American (AMR) AF: 0.920 AC: 14013 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3249 AN: 3468

East Asian (EAS) AF: 0.997 AC: 5144 AN: 5162

South Asian (SAS) AF: 0.920 AC: 4422 AN: 4808

European-Finnish (FIN) AF: 0.911 AC: 9384 AN: 10306

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61309 AN: 67872

Other (OTH) AF: 0.892 AC: 1876 AN: 2104

Alfa AF: 0.889 Hom.: 21559

Bravo AF: 0.868

Asia WGS AF: 0.925 AC: 3211 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.035
DANN	Benign	0.63
PhyloP100		-1.6
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: rs7591305; hg19: chr2-109491444; COSMIC: COSV54565714; COSMIC: COSV54565714;