rs1048197

chr6-109441129-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003080.3(SMPD2):c.8C>T(p.Pro3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 1,614,028 control chromosomes in the GnomAD database, including 3,581 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.060 (410 hom., cov: 32)
  • Exomes 𝑓: 0.049 (3171 hom.)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580

Genes affected

SMPD2 (HGNC:11121): (sphingomyelin phosphodiesterase 2) This gene encodes a protein which was initially identified as a sphingomyelinase based on sequence similarity between bacterial sphingomyelinases and a yeast protein. Subsequent studies showed that its biological function is less likely to be as a sphingomyelinase and instead as a lysophospholipase. [provided by RefSeq, Oct 2009]

PPIL6 (HGNC:21557): (peptidylprolyl isomerase like 6) Predicted to enable peptidyl-prolyl cis-trans isomerase activity. Predicted to be involved in protein folding and protein peptidyl-prolyl isomerization. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012243986).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD2	NM_003080.3	c.8C>T	p.Pro3Leu	missense_variant	1/10	ENST00000258052.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD2	ENST00000258052.8	c.8C>T	p.Pro3Leu	missense_variant	1/10	1	NM_003080.3	P1
PPIL6	ENST00000440797.6	c.-539G>A		5_prime_UTR_variant	1/9	1
PPIL6	ENST00000424445.6	c.-539G>A		5_prime_UTR_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9176 AN: 152148 Hom.: 409 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0426

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0621

GnomAD3 exomes AF: 0.0794 AC: 19951 AN: 251324 Hom.: 1294 AF XY: 0.0770 AC XY: 10468 AN XY: 135862

Gnomad AFR exome AF: 0.0553

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.0693

Gnomad NFE exome AF: 0.0351

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0494 AC: 72251 AN: 1461762 Hom.: 3171 Cov.: 32 AF XY: 0.0511 AC XY: 37123 AN XY: 727184

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.0453

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.0656

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0604

GnomAD4 genome AF: 0.0604 AC: 9196 AN: 152266 Hom.: 410 Cov.: 32 AF XY: 0.0666 AC XY: 4955 AN XY: 74440

Gnomad4 AFR AF: 0.0546

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0426

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0744

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0619

Alfa AF: 0.0438 Hom.: 554

Bravo AF: 0.0636

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0332 AC: 128

ESP6500AA AF: 0.0545 AC: 240

ESP6500EA AF: 0.0360 AC: 310

ExAC AF: 0.0748 AC: 9082

Asia WGS AF: 0.178 AC: 617 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0395

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.4e-16	P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.060
Sift	Benign	0.17	T
Sift4G	Benign	0.40	T
Polyphen		0.011	B
Vest4		0.050
MPC		0.076
ClinPred		0.034	T
GERP RS		4.3
Varity_R		0.057
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1048197; hg19: chr6-109762332; COSMIC: COSV57804175; COSMIC: COSV57804175;