rs1048197

Variant names:

• chr6-109441129-C-T
• rs1048197
• NM_003080.3:c.8C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003080.3. 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
	SMPD2	NM_003080.3	MANE Select	c.8C>T	p.Pro3Leu	missense	Exon 1 of 10	NP_003071.2
	PPIL6	NR_104429.1		n.43G>A		non_coding_transcript_exon	Exon 1 of 9
	PPIL6	NM_001111298.2		c.-539G>A		5_prime_UTR	Exon 1 of 9	NP_001104768.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD2	ENST00000258052.8	TSL:1 MANE Select	c.8C>T	p.Pro3Leu	missense	Exon 1 of 10	ENSP00000258052.3
	PPIL6	ENST00000440797.6	TSL:1	c.-539G>A		5_prime_UTR	Exon 1 of 9	ENSP00000392257.2
	PPIL6	ENST00000424445.6	TSL:5	c.-539G>A		5_prime_UTR	Exon 1 of 7	ENSP00000407731.2

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

GnomAD2 exomes AF: 0.0794 AC: 19951 AN: 251324 AF XY: 0.0770

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 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

African (AFR) AF: 0.0525 AC: 1756 AN: 33476

American (AMR) AF: 0.152 AC: 6784 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 1183 AN: 26136

East Asian (EAS) AF: 0.205 AC: 8135 AN: 39698

South Asian (SAS) AF: 0.126 AC: 10826 AN: 86244

European-Finnish (FIN) AF: 0.0656 AC: 3502 AN: 53408

Middle Eastern (MID) AF: 0.0683 AC: 394 AN: 5768

European-Non Finnish (NFE) AF: 0.0324 AC: 36021 AN: 1111932

Other (OTH) AF: 0.0604 AC: 3650 AN: 60392

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

African (AFR) AF: 0.0546 AC: 2271 AN: 41562

American (AMR) AF: 0.119 AC: 1819 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 148 AN: 3472

East Asian (EAS) AF: 0.204 AC: 1051 AN: 5152

South Asian (SAS) AF: 0.137 AC: 663 AN: 4826

European-Finnish (FIN) AF: 0.0744 AC: 790 AN: 10612

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2291 AN: 68022

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0451 Hom.: 1180

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 v4.9

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
PhyloP100		0.058
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
PromoterAI		-0.030	Neutral
Varity_R		0.057
gMVP		0.46
Mutation Taster		=98/2	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: rs1048197; hg19: chr6-109762332; COSMIC: COSV57804175; COSMIC: COSV57804175;