NM_144978.3:c.1694-542A>G

Variant names:

• chr2-108872909-A-G
• rs1073893
• NM_144978.3:c.1694-542A>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.1694-542A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 152,070 control chromosomes in the GnomAD database, including 43,121 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 0.73 (43121 hom., cov: 31)
• Consequence: CCDC138 NM_144978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 6 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC138	NM_144978.3	c.1694-542A>G		intron_variant	Intron 13 of 14	ENST00000295124.9	NP_659415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC138	ENST00000295124.9	c.1694-542A>G		intron_variant	Intron 13 of 14	2	NM_144978.3	ENSP00000295124.4
CCDC138	ENST00000412964.6	c.1694-3179A>G		intron_variant	Intron 13 of 13	1		ENSP00000411800.2
CCDC138	ENST00000608781.1	c.44-9762A>G		intron_variant	Intron 1 of 2	3		ENSP00000477316.1
CCDC138	ENST00000409529.6	n.*1499-3179A>G		intron_variant	Intron 13 of 13	2		ENSP00000386418.2

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110788 AN: 151952 Hom.: 43113 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.832

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.729 AC: 110823 AN: 152070 Hom.: 43121 Cov.: 31 AF XY: 0.735 AC XY: 54635 AN XY: 74368

African (AFR) AF: 0.430 AC: 17801 AN: 41428

American (AMR) AF: 0.833 AC: 12734 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3062 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4916 AN: 5180

South Asian (SAS) AF: 0.750 AC: 3608 AN: 4812

European-Finnish (FIN) AF: 0.893 AC: 9441 AN: 10578

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56684 AN: 67994

Other (OTH) AF: 0.779 AC: 1643 AN: 2110

Alfa AF: 0.693 Hom.: 2598

Bravo AF: 0.715

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.75
DANN	Benign	0.57
PhyloP100		-1.5
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: rs1073893; hg19: chr2-109489365;