2-109614582-C-A

Variant names:

• chr2-109614582-C-A
• rs571248763
• NM_023016.4:c.93C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023016.4(SOWAHC):​c.93C>A​(p.His31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,407,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: SOWAHC NM_023016.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.356

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008046806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOWAHC	NM_023016.4	c.93C>A	p.His31Gln	missense_variant	Exon 1 of 1	ENST00000356454.5	NP_075392.2
RANBP2	XM_047445367.1	c.8371-226822C>A		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOWAHC	ENST00000356454.5	c.93C>A	p.His31Gln	missense_variant	Exon 1 of 1	6	NM_023016.4	ENSP00000365830.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 151662 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 7 AN: 50032 Hom.: 0 AF XY: 0.000101 AC XY: 3 AN XY: 29614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.000716

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000938

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000868 AC: 109 AN: 1255568 Hom.: 0 Cov.: 29 AF XY: 0.0000925 AC XY: 57 AN XY: 616492

Gnomad4 AFR exome AF: 0.0000789

Gnomad4 AMR exome AF: 0.0000527

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000807

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000552

Gnomad4 OTH exome AF: 0.000156

GnomAD4 genome AF: 0.000138 AC: 21 AN: 151770 Hom.: 0 Cov.: 35 AF XY: 0.000135 AC XY: 10 AN XY: 74178

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000493 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.93C>A (p.H31Q) alteration is located in exon 1 (coding exon 1) of the SOWAHC gene. This alteration results from a C to A substitution at nucleotide position 93, causing the histidine (H) at amino acid position 31 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.1
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.016
Sift	Benign	0.35	T
Sift4G	Benign	0.31	T
Polyphen		0.031	B
Vest4		0.10
MutPred		0.37		Loss of methylation at R28 (P = 0.0452);
MVP		0.014
ClinPred		0.048	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.046
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs571248763; hg19: chr2-110372159;