2-109614696-T-C

Variant names:

• chr2-109614696-T-C
• rs745896353
• NM_023016.4:c.207T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_023016.4(SOWAHC):​c.207T>C​(p.Asp69Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,232 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: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: SOWAHC NM_023016.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.850
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.85 with no splicing effect.

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.207T>C	p.Asp69Asp	synonymous	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.207T>C	p.Asp69Asp	synonymous	Exon 1 of 1	ENSP00000365830.2	Q53LP3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1336232 Hom.: 0 Cov.: 35 AF XY: 0.00000152 AC XY: 1 AN XY: 659146

⚠️ 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: 27098

American (AMR) AF: 0.00 AC: 0 AN: 29596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23632

East Asian (EAS) AF: 0.00 AC: 0 AN: 29168

South Asian (SAS) AF: 0.00 AC: 0 AN: 74776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5008

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1055816

Other (OTH) AF: 0.00 AC: 0 AN: 55554

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		-0.85
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	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: rs745896353; hg19: chr2-110372273;