NM_144978.3:c.94-2dupA

Variant names:

• chr2-108788029-T-TA
• rs35693674
• NM_144978.3:c.94-2dupA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_144978.3(CCDC138):​c.94-2dupA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,378,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CCDC138 NM_144978.3 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25
• Publications: 2 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029029028 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.2, offset of 0 (no position change), new splice context is: cttttctttttttttttaAGtat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	NM_144978.3	MANE Select	c.94-2dupA		splice_acceptor intron	N/A	NP_659415.1	Q96M89-1
	CCDC138	NM_001351544.2		c.112-2dupA		splice_acceptor intron	N/A	NP_001338473.1
	CCDC138	NM_001351545.1		c.137-822dupA		intron	N/A	NP_001338474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	ENST00000295124.9	TSL:2 MANE Select	c.94-3_94-2insA		splice_acceptor intron	N/A	ENSP00000295124.4	Q96M89-1
	CCDC138	ENST00000412964.6	TSL:1	c.94-3_94-2insA		splice_acceptor intron	N/A	ENSP00000411800.2	Q96M89-2
	CCDC138	ENST00000925777.1		c.94-3_94-2insA		splice_acceptor intron	N/A	ENSP00000595836.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000140 AC: 3 AN: 214564 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000400

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000985

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1378202 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 687980

African (AFR) AF: 0.00 AC: 0 AN: 29752

American (AMR) AF: 0.0000292 AC: 1 AN: 34214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24456

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52412

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4430

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059140

Other (OTH) AF: 0.00 AC: 0 AN: 57048

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.43		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35693674; hg19: chr2-109404485;