chr2-108791715-C-A

Variant names:

• chr2-108791715-C-A
• rs1679936009
• NM_144978.3:c.307C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144978.3(CCDC138):​c.307C>A​(p.Gln103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC138 NM_144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.207
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04690233).

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.307C>A	p.Gln103Lys	missense	Exon 4 of 15	NP_659415.1	Q96M89-1
	CCDC138	NM_001351544.2		c.325C>A	p.Gln109Lys	missense	Exon 4 of 15	NP_001338473.1
	CCDC138	NM_001351545.1		c.292C>A	p.Gln98Lys	missense	Exon 3 of 14	NP_001338474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	ENST00000295124.9	TSL:2 MANE Select	c.307C>A	p.Gln103Lys	missense	Exon 4 of 15	ENSP00000295124.4	Q96M89-1
	CCDC138	ENST00000412964.6	TSL:1	c.307C>A	p.Gln103Lys	missense	Exon 4 of 14	ENSP00000411800.2	Q96M89-2
	CCDC138	ENST00000925777.1		c.307C>A	p.Gln103Lys	missense	Exon 4 of 16	ENSP00000595836.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151964 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454752 Hom.: 0 Cov.: 30 AF XY: 0.00000691 AC XY: 5 AN XY: 723574

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 85070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107552

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151964 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74226

African (AFR) AF: 0.00 AC: 0 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.9
DANN	Benign	0.36
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.21
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.022	B
Vest4		0.074
MutPred		0.25		Gain of ubiquitination at Q103 (P = 0.0121)
MVP		0.83
MPC		0.063
ClinPred		0.031	T
GERP RS		3.0
PromoterAI		-0.043	Neutral
Varity_R		0.058
gMVP		0.064
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1679936009; hg19: chr2-109408171;