chr2-230212397-G-A

Variant names:

• chr2-230212397-G-A
• rs28930679
• NM_080424.4:c.617C>T

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.617C>T​(p.Ala206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,606,272 control chromosomes in the GnomAD database, including 44,658 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A206E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (3464 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41194 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0930
• Publications: 24 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=0.010025024).
• BP6: Variant 2-230212397-G-A is Benign according to our data. Variant chr2-230212397-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 334911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	NM_080424.4	MANE Select	c.617C>T	p.Ala206Val	missense	Exon 5 of 19	NP_536349.3
	SP110	NM_001378442.1		c.635C>T	p.Ala212Val	missense	Exon 6 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.617C>T	p.Ala206Val	missense	Exon 5 of 19	NP_001365372.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	ENST00000258381.11	TSL:2 MANE Select	c.617C>T	p.Ala206Val	missense	Exon 5 of 19	ENSP00000258381.6
	SP110	ENST00000358662.9	TSL:1	c.617C>T	p.Ala206Val	missense	Exon 5 of 18	ENSP00000351488.4
	SP110	ENST00000258382.10	TSL:1	c.617C>T	p.Ala206Val	missense	Exon 5 of 15	ENSP00000258382.5

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31231 AN: 151984 Hom.: 3464 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0972

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.214 AC: 53736 AN: 250976 AF XY: 0.215

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0847

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.234 AC: 340263 AN: 1454170 Hom.: 41194 Cov.: 32 AF XY: 0.233 AC XY: 168649 AN XY: 723754

African (AFR) AF: 0.144 AC: 4824 AN: 33384

American (AMR) AF: 0.243 AC: 10845 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 7452 AN: 26084

East Asian (EAS) AF: 0.107 AC: 4255 AN: 39668

South Asian (SAS) AF: 0.180 AC: 15466 AN: 86106

European-Finnish (FIN) AF: 0.207 AC: 11064 AN: 53362

Middle Eastern (MID) AF: 0.271 AC: 1559 AN: 5752

European-Non Finnish (NFE) AF: 0.245 AC: 270897 AN: 1104954

Other (OTH) AF: 0.231 AC: 13901 AN: 60160

GnomAD4 genome AF: 0.205 AC: 31238 AN: 152102 Hom.: 3464 Cov.: 32 AF XY: 0.203 AC XY: 15126 AN XY: 74372

African (AFR) AF: 0.142 AC: 5899 AN: 41482

American (AMR) AF: 0.220 AC: 3366 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 994 AN: 3472

East Asian (EAS) AF: 0.0967 AC: 501 AN: 5182

South Asian (SAS) AF: 0.166 AC: 798 AN: 4820

European-Finnish (FIN) AF: 0.211 AC: 2226 AN: 10572

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16644 AN: 67974

Other (OTH) AF: 0.233 AC: 492 AN: 2114

Alfa AF: 0.228 Hom.: 7589

Bravo AF: 0.206

TwinsUK AF: 0.243 AC: 901

ALSPAC AF: 0.257 AC: 992

ESP6500AA AF: 0.141 AC: 623

ESP6500EA AF: 0.253 AC: 2177

ExAC AF: 0.211 AC: 25613

Asia WGS AF: 0.107 AC: 375 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.258

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hepatic veno-occlusive disease-immunodeficiency syndrome (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.7
DANN	Benign	0.89
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.093
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.043
Sift	Benign	0.050	D
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.051
MPC		0.13
ClinPred		0.00012	T
GERP RS		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.11
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: rs28930679; hg19: chr2-231077112; COSMIC: COSV51249759; COSMIC: COSV51249759;