2-109614878-A-T

Variant names:

• chr2-109614878-A-T
• rs1197419922
• NM_023016.4:c.389A>T

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.389A>T​(p.Gln130Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,423,024 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SOWAHC NM_023016.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.62
• 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=0.03609073).

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.389A>T	p.Gln130Leu	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.389A>T	p.Gln130Leu	missense	Exon 1 of 1	ENSP00000365830.2	Q53LP3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151786 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000197 AC: 25 AN: 1271238 Hom.: 0 Cov.: 35 AF XY: 0.0000258 AC XY: 16 AN XY: 620236

African (AFR) AF: 0.00 AC: 0 AN: 24676

American (AMR) AF: 0.00 AC: 0 AN: 17660

Ashkenazi Jewish (ASJ) AF: 0.0000549 AC: 1 AN: 18228

East Asian (EAS) AF: 0.00 AC: 0 AN: 30338

South Asian (SAS) AF: 0.00 AC: 0 AN: 60898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3610

European-Non Finnish (NFE) AF: 0.0000223 AC: 23 AN: 1032472

Other (OTH) AF: 0.0000190 AC: 1 AN: 52742

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151786 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74148

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.0000658 AC: 1 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000290 AC: 1 AN: 3460

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	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.039
DANN	Benign	0.74
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-3.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.015
Sift	Benign	0.34	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.17		Loss of glycosylation at S126 (P = 0.1235)
MVP		0.014
ClinPred		0.084	T
GERP RS		-5.9
Varity_R		0.035
gMVP		0.19
Mutation Taster		=96/4	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: rs1197419922; hg19: chr2-110372455;