2-109614533-C-G

Variant names:

• chr2-109614533-C-G
• rs1480545963
• NM_023016.4:c.44C>G

Variant summary

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

The NM_023016.4(SOWAHC):​c.44C>G​(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000088 in 1,136,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: SOWAHC NM_023016.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 0 publications found

Genes affected

SOWAHC (HGNC:26149): (sosondowah ankyrin repeat domain family member C)

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=0.03303787).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023016.4. 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
	SOWAHC	NM_023016.4	MANE Select	c.44C>G	p.Pro15Arg	missense	Exon 1 of 1	NP_075392.2	Q53LP3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOWAHC	ENST00000356454.5	TSL:6 MANE Select	c.44C>G	p.Pro15Arg	missense	Exon 1 of 1	ENSP00000365830.2	Q53LP3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 8.80e-7 AC: 1 AN: 1136262 Hom.: 0 Cov.: 29 AF XY: 0.00000183 AC XY: 1 AN XY: 547210

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

African (AFR) AF: 0.00 AC: 0 AN: 22826

American (AMR) AF: 0.00 AC: 0 AN: 8372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14688

East Asian (EAS) AF: 0.00 AC: 0 AN: 25992

South Asian (SAS) AF: 0.00 AC: 0 AN: 33878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3028

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 956950

Other (OTH) AF: 0.00 AC: 0 AN: 45742

⚠️ 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.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.062
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.015
Sift	Benign	0.72	T
Sift4G	Benign	0.68	T
Polyphen		0.0040	B
Vest4		0.053
MutPred		0.22		Gain of MoRF binding (P = 0.0102)
MVP		0.040
ClinPred		0.081	T
GERP RS		0.67
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.21
Mutation Taster		=95/5	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: rs1480545963; hg19: chr2-110372110;