2-230207994-C-T

Variant names:

• chr2-230207994-C-T
• rs1365776
• NM_080424.4:c.895G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 49 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 -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 VariationId is 334909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080424.4. 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
	SP110	NM_080424.4	MANE Select	c.895G>A	p.Gly299Arg	missense	Exon 8 of 19	NP_536349.3	Q9HB58-6
	SP110	NM_001378442.1		c.913G>A	p.Gly305Arg	missense	Exon 9 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.895G>A	p.Gly299Arg	missense	Exon 8 of 19	NP_001365372.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	ENST00000258381.11	TSL:2 MANE Select	c.895G>A	p.Gly299Arg	missense	Exon 8 of 19	ENSP00000258381.6	Q9HB58-6
	SP110	ENST00000358662.9	TSL:1	c.895G>A	p.Gly299Arg	missense	Exon 8 of 18	ENSP00000351488.4	Q9HB58-1
	SP110	ENST00000258382.10	TSL:1	c.895G>A	p.Gly299Arg	missense	Exon 8 of 15	ENSP00000258382.5	Q9HB58-3

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

GnomAD2 exomes AF: 0.687 AC: 159179 AN: 231746 AF XY: 0.677

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 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

African (AFR) AF: 0.925 AC: 28957 AN: 31298

American (AMR) AF: 0.800 AC: 34955 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 16477 AN: 25172

East Asian (EAS) AF: 0.863 AC: 33808 AN: 39182

South Asian (SAS) AF: 0.708 AC: 58846 AN: 83108

European-Finnish (FIN) AF: 0.583 AC: 30602 AN: 52494

Middle Eastern (MID) AF: 0.724 AC: 4030 AN: 5570

European-Non Finnish (NFE) AF: 0.583 AC: 599153 AN: 1027242

Other (OTH) AF: 0.650 AC: 36828 AN: 56670

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

African (AFR) AF: 0.912 AC: 37871 AN: 41538

American (AMR) AF: 0.773 AC: 11816 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2304 AN: 3472

East Asian (EAS) AF: 0.886 AC: 4590 AN: 5182

South Asian (SAS) AF: 0.712 AC: 3435 AN: 4824

European-Finnish (FIN) AF: 0.598 AC: 6329 AN: 10592

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40254 AN: 67988

Other (OTH) AF: 0.728 AC: 1537 AN: 2112

Alfa AF: 0.635 Hom.: 127085

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hepatic veno-occlusive disease-immunodeficiency syndrome (3)
-	-	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.23
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.024
Sift	Benign	0.69	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.28		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
Mutation Taster		=99/1	polymorphism (auto)

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: rs1365776; hg19: chr2-231072709; COSMIC: COSV107250542; COSMIC: COSV107250542;