chr19-2353033-C-T

Variant names:

• chr19-2353033-C-T
• NM_152988.3:c.1603C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152988.3(SPPL2B):​c.1603C>T​(p.Pro535Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPPL2B NM_152988.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0860

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062421083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2B	NM_152988.3	c.1603C>T	p.Pro535Ser	missense_variant	Exon 15 of 15	ENST00000613503.5	NP_694533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2B	ENST00000613503.5	c.1603C>T	p.Pro535Ser	missense_variant	Exon 15 of 15	1	NM_152988.3	ENSP00000478298.1
SPPL2B	ENST00000610743.4	c.*130C>T		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000478510.1
SPPL2B	ENST00000589515.2	n.1199C>T		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1603C>T (p.P535S) alteration is located in exon 15 (coding exon 15) of the SPPL2B gene. This alteration results from a C to T substitution at nucleotide position 1603, causing the proline (P) at amino acid position 535 to be replaced by a serine (S). 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	0.068
BayesDel_addAF	Benign	-0.0051	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.2
DANN	Benign	0.84
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.062	T
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.59	T
Polyphen		0.011	B
Vest4		0.068
MVP		0.055
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2353031;