rs1395510972

Variant names:

• chr2-108786903-C-A
• rs1395510972
• NM_144978.3:c.81C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-108786903-C-A
• chr2-108786903-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303106.2(CCDC138):​c.-863C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CCDC138 NM_001303106.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12342873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303106.2. 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.81C>A	p.Ser27Arg	missense	Exon 1 of 15	NP_659415.1	Q96M89-1
	CCDC138	NM_001303106.2		c.-863C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001290035.1
	CCDC138	NM_001351544.2		c.81C>A	p.Ser27Arg	missense	Exon 1 of 15	NP_001338473.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC138	ENST00000295124.9	TSL:2 MANE Select	c.81C>A	p.Ser27Arg	missense	Exon 1 of 15	ENSP00000295124.4	Q96M89-1
	CCDC138	ENST00000412964.6	TSL:1	c.81C>A	p.Ser27Arg	missense	Exon 1 of 14	ENSP00000411800.2	Q96M89-2
	CCDC138	ENST00000925777.1		c.81C>A	p.Ser27Arg	missense	Exon 1 of 16	ENSP00000595836.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394000 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690124

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000343 AC: 1 AN: 29150

American (AMR) AF: 0.00 AC: 0 AN: 34246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23960

East Asian (EAS) AF: 0.00 AC: 0 AN: 33110

South Asian (SAS) AF: 0.00 AC: 0 AN: 79454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4926

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081162

Other (OTH) AF: 0.00 AC: 0 AN: 57512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.12
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.21	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.19		Loss of phosphorylation at S27 (P = 0.039)
MVP		0.78
MPC		0.17
ClinPred		0.18	T
GERP RS		0.74
PromoterAI		-0.0098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.064
gMVP		0.039
Mutation Taster		=98/2	polymorphism

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: rs1395510972; hg19: chr2-109403359;