2-230213010-A-G

Variant names:

• chr2-230213010-A-G
• rs1129411
• NM_080424.4:c.334T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378442.1(SP110):​c.352T>C​(p.Trp118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,613,738 control chromosomes in the GnomAD database, including 641,644 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W118G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.92 (64041 hom., cov: 30)
  • Exomes 𝑓: 0.89 (577603 hom.)
• Consequence: SP110 NM_001378442.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.189
• Publications: 33 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=8.1801585E-7).
• BP6: Variant 2-230213010-A-G is Benign according to our data. Variant chr2-230213010-A-G is described in ClinVar as Benign. ClinVar VariationId is 403465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378442.1. 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.334T>C	p.Trp112Arg	missense	Exon 4 of 19	NP_536349.3
	SP110	NM_001378442.1		c.352T>C	p.Trp118Arg	missense	Exon 5 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.334T>C	p.Trp112Arg	missense	Exon 4 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.334T>C	p.Trp112Arg	missense	Exon 4 of 19	ENSP00000258381.6
	SP110	ENST00000358662.9	TSL:1	c.334T>C	p.Trp112Arg	missense	Exon 4 of 18	ENSP00000351488.4
	SP110	ENST00000258382.10	TSL:1	c.334T>C	p.Trp112Arg	missense	Exon 4 of 15	ENSP00000258382.5

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139312 AN: 152002 Hom.: 63987 Cov.: 30

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.914

GnomAD2 exomes AF: 0.910 AC: 226551 AN: 248960 AF XY: 0.909

Gnomad AFR exome AF: 0.981

Gnomad AMR exome AF: 0.936

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.868

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.888 AC: 1298374 AN: 1461618 Hom.: 577603 Cov.: 55 AF XY: 0.890 AC XY: 646874 AN XY: 727134

African (AFR) AF: 0.982 AC: 32867 AN: 33480

American (AMR) AF: 0.935 AC: 41824 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 24246 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39649 AN: 39700

South Asian (SAS) AF: 0.937 AC: 80856 AN: 86256

European-Finnish (FIN) AF: 0.865 AC: 46167 AN: 53388

Middle Eastern (MID) AF: 0.914 AC: 5273 AN: 5766

European-Non Finnish (NFE) AF: 0.875 AC: 973199 AN: 1111782

Other (OTH) AF: 0.899 AC: 54293 AN: 60388

GnomAD4 genome AF: 0.917 AC: 139425 AN: 152120 Hom.: 64041 Cov.: 30 AF XY: 0.917 AC XY: 68175 AN XY: 74336

African (AFR) AF: 0.978 AC: 40575 AN: 41500

American (AMR) AF: 0.919 AC: 14043 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3207 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5149 AN: 5162

South Asian (SAS) AF: 0.942 AC: 4533 AN: 4810

European-Finnish (FIN) AF: 0.867 AC: 9181 AN: 10590

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.879 AC: 59748 AN: 67992

Other (OTH) AF: 0.912 AC: 1918 AN: 2102

Alfa AF: 0.895 Hom.: 159763

Bravo AF: 0.922

TwinsUK AF: 0.872 AC: 3235

ALSPAC AF: 0.879 AC: 3387

ESP6500AA AF: 0.976 AC: 4300

ESP6500EA AF: 0.883 AC: 7598

ExAC AF: 0.909 AC: 110371

Asia WGS AF: 0.962 AC: 3345 AN: 3478

EpiCase AF: 0.885

EpiControl AF: 0.879

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hepatic veno-occlusive disease-immunodeficiency syndrome (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.30
DANN	Benign	0.48
DEOGEN2	Benign	0.00094	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.19
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.28
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.45		Gain of disorder (P = 0.0043)
MPC		0.24
ClinPred		0.0023	T
GERP RS		-0.86
Varity_R		0.023
gMVP		0.18
Mutation Taster		=100/0	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: rs1129411; hg19: chr2-231077725; COSMIC: COSV99283204; COSMIC: COSV99283204;