2-230207994-C-T

Position:

• chr2-230207994-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080424.4(SP110):​c.895G>A​(p.Gly299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,516,630 control chromosomes in the GnomAD database, including 307,027 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40643 hom., cov: 32)
  • Exomes 𝑓: 0.62 (266384 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.235

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.527673E-7).
• BP6: Variant 2-230207994-C-T is Benign according to our data. Variant chr2-230207994-C-T is described in ClinVar as [Benign]. Clinvar id is 334909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-230207994-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.895G>A	p.Gly299Arg	missense_variant	8/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.895G>A	p.Gly299Arg	missense_variant	8/19	2	NM_080424.4	P1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108794 AN: 152084 Hom.: 40579 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.728

GnomAD3 exomes AF: 0.687 AC: 159179 AN: 231746 Hom.: 56296 AF XY: 0.677 AC XY: 84734 AN XY: 125154

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.897

Gnomad SAS exome AF: 0.707

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.674

GnomAD4 exome AF: 0.618 AC: 843656 AN: 1364428 Hom.: 266384 Cov.: 22 AF XY: 0.620 AC XY: 423576 AN XY: 682958

Gnomad4 AFR exome AF: 0.925

Gnomad4 AMR exome AF: 0.800

Gnomad4 ASJ exome AF: 0.655

Gnomad4 EAS exome AF: 0.863

Gnomad4 SAS exome AF: 0.708

Gnomad4 FIN exome AF: 0.583

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.716 AC: 108915 AN: 152202 Hom.: 40643 Cov.: 32 AF XY: 0.719 AC XY: 53543 AN XY: 74432

Gnomad4 AFR AF: 0.912

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.664

Gnomad4 EAS AF: 0.886

Gnomad4 SAS AF: 0.712

Gnomad4 FIN AF: 0.598

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.728

Alfa AF: 0.628 Hom.: 65724

Bravo AF: 0.739

TwinsUK AF: 0.581 AC: 2155

ALSPAC AF: 0.604 AC: 2329

ESP6500AA AF: 0.895 AC: 3941

ESP6500EA AF: 0.603 AC: 5186

ExAC AF: 0.665 AC: 80094

Asia WGS AF: 0.778 AC: 2704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatic veno-occlusive disease-immunodeficiency syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.50
DANN	Benign	0.67
DEOGEN2	Benign	0.0013	.;T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.39	T;T;T;T;T
MetaRNN	Benign	8.5e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.69	T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.10
MutPred		0.28		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;
MPC		0.65
ClinPred		0.0054	T
GERP RS		-0.14
Varity_R		0.033
gMVP		0.033

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: rs1365776; hg19: chr2-231072709;