19-2339960-C-G

Variant names:

• chr19-2339960-C-G
• rs200233967
• NM_152988.3:c.736C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152988.3(SPPL2B):​c.736C>G​(p.Leu246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,553,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: SPPL2B NM_152988.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

SPPL2B (HGNC:30627): (signal peptide peptidase like 2B) This gene encodes a member of the GXGD family of aspartic proteases. The GXGD proteases are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions. This enzyme localizes to endosomes, lysosomes, and the plasma membrane. It cleaves the transmembrane domain of tumor necrosis factor alpha to release the intracellular domain, which triggers cytokine expression in the innate and adaptive immunity pathways. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000273734 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07992467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2B	NM_152988.3	c.736C>G	p.Leu246Val	missense_variant	Exon 6 of 15	ENST00000613503.5	NP_694533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2B	ENST00000613503.5	c.736C>G	p.Leu246Val	missense_variant	Exon 6 of 15	1	NM_152988.3	ENSP00000478298.1
ENSG00000273734	ENST00000621615.1	n.*423C>G		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000481965.1
ENSG00000273734	ENST00000621615.1	n.*423C>G		3_prime_UTR_variant	Exon 6 of 8	2		ENSP00000481965.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152210 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000264 AC: 42 AN: 158824 Hom.: 0 AF XY: 0.000226 AC XY: 19 AN XY: 84178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.000468

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.000428 AC: 600 AN: 1401128 Hom.: 0 Cov.: 56 AF XY: 0.000409 AC XY: 283 AN XY: 691402

Gnomad4 AFR exome AF: 0.0000631

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.000477

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.000396

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152210 Hom.: 0 Cov.: 36 AF XY: 0.000242 AC XY: 18 AN XY: 74354

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000380 Hom.: 0

ExAC AF: 0.000285 AC: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736C>G (p.L246V) alteration is located in exon 6 (coding exon 6) of the SPPL2B gene. This alteration results from a C to G substitution at nucleotide position 736, causing the leucine (L) at amino acid position 246 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Benign	0.45
DEOGEN2	Benign	0.029	T;T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	T;D;T;D
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.47	N;.;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.27	B;.;B;B
Vest4		0.17
MVP		0.014
ClinPred		0.065	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.025
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs200233967; hg19: chr19-2339959;