2-230212440-G-C

Variant names:

• chr2-230212440-G-C
• rs148591984
• NM_080424.4:c.584-10C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_080424.4(SP110):​c.584-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,586,492 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: SP110 NM_080424.4 intron
• Scores: Splicing: ADA: 0.002571
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0850
• Publications: 0 publications found

Genes affected

SP110 (HGNC:5401): (SP110 nuclear body protein) The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This gene is a member of the SP100/SP140 family of nuclear body proteins and encodes a leukocyte-specific nuclear body component. The protein can function as an activator of gene transcription and may serve as a nuclear hormone receptor coactivator. In addition, it has been suggested that the protein may play a role in ribosome biogenesis and in the induction of myeloid cell differentiation. Alternative splicing has been observed for this gene and three transcript variants, encoding distinct isoforms, have been identified. [provided by RefSeq, Jul 2008]

SP140 (HGNC:17133): (SP140 nuclear body protein) This gene encodes a member of the SP100 family of proteins, which are share common domains including an N-terminal homogeneously staining region domain followed by a SP100/autoimmune regulator/NucP41/P75/deformed epidermal autoregulatory factor domain, a plant homeobox zinc finger, and a bromodomain. The encoded protein is interferon-inducible and is expressed at high levels in the nuclei of leukocytes. Variants of this gene have been associated with multiple sclerosis, Crohn's disease, and chronic lymphocytic leukemia. Alternative splicing results in multiple variants. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-230212440-G-C is Benign according to our data. Variant chr2-230212440-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334913.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0019 (289/152330) while in subpopulation NFE AF = 0.00334 (227/68036). AF 95% confidence interval is 0.00298. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP110	NM_080424.4	c.584-10C>G		intron_variant	Intron 4 of 18	ENST00000258381.11	NP_536349.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP110	ENST00000258381.11	c.584-10C>G		intron_variant	Intron 4 of 18	2	NM_080424.4	ENSP00000258381.6

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00197 AC: 496 AN: 251204 AF XY: 0.00191

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00284 AC: 4068 AN: 1434162 Hom.: 10 Cov.: 28 AF XY: 0.00277 AC XY: 1980 AN XY: 715142

African (AFR) AF: 0.000424 AC: 14 AN: 33010

American (AMR) AF: 0.00192 AC: 86 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25916

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85732

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53400

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.00346 AC: 3762 AN: 1086666

Other (OTH) AF: 0.00251 AC: 149 AN: 59440

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74480

African (AFR) AF: 0.000481 AC: 20 AN: 41572

American (AMR) AF: 0.00170 AC: 26 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hepatic veno-occlusive disease-immunodeficiency syndrome Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Mycobacterium tuberculosis, susceptibility to;C1856128:Hepatic veno-occlusive disease-immunodeficiency syndrome Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SP110 NM_004509.3 exon 5 c.584-10C>G: This variant has not been reported in the literature but is present in 0.3% (446/128970) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-231077155-G-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:334913). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

SP110-related disorder Benign:1

Oct 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.64
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.020		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: rs148591984; hg19: chr2-231077155;