2-108846060-A-T

Variant names:

• chr2-108846060-A-T
• rs10496425
• NM_144978.3:c.1324-678A>T

Variant summary

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

The NM_144978.3(CCDC138):​c.1324-678A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 152,214 control chromosomes in the GnomAD database, including 63,702 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 0.91 (63702 hom., cov: 31)
• Consequence: CCDC138 NM_144978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458
• Publications: 3 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC138	NM_144978.3	c.1324-678A>T		intron_variant	Intron 11 of 14	ENST00000295124.9	NP_659415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC138	ENST00000295124.9	c.1324-678A>T		intron_variant	Intron 11 of 14	2	NM_144978.3	ENSP00000295124.4
CCDC138	ENST00000412964.6	c.1324-678A>T		intron_variant	Intron 11 of 13	1		ENSP00000411800.2
CCDC138	ENST00000456512.1	c.1012-678A>T		intron_variant	Intron 8 of 8	5		ENSP00000392385.1
CCDC138	ENST00000409529.6	n.*1129-678A>T		intron_variant	Intron 11 of 13	2		ENSP00000386418.2

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139044 AN: 152094 Hom.: 63644 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.898

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.921

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

GnomAD4 genome AF: 0.914 AC: 139163 AN: 152214 Hom.: 63702 Cov.: 31 AF XY: 0.916 AC XY: 68166 AN XY: 74428

African (AFR) AF: 0.923 AC: 38312 AN: 41506

American (AMR) AF: 0.938 AC: 14344 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3193 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5149 AN: 5166

South Asian (SAS) AF: 0.920 AC: 4445 AN: 4832

European-Finnish (FIN) AF: 0.911 AC: 9662 AN: 10610

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61089 AN: 68020

Other (OTH) AF: 0.922 AC: 1947 AN: 2112

Alfa AF: 0.903 Hom.: 7714

Bravo AF: 0.917

Asia WGS AF: 0.939 AC: 3267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.35
DANN	Benign	0.25
PhyloP100		-0.46
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: rs10496425; hg19: chr2-109462516; COSMIC: COSV54565592;