chr6-109441365-C-T

Variant names:

• chr6-109441365-C-T
• rs758916713
• NM_003080.3:c.59C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003080.3(SMPD2):​c.59C>T​(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3296098).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD2	NM_003080.3	MANE Select	c.59C>T	p.Pro20Leu	missense	Exon 2 of 10	NP_003071.2	O60906
	PPIL6	NM_001111298.2		c.-775G>A		upstream_gene	N/A	NP_001104768.2	Q8IXY8-2
	PPIL6	NM_001286360.1		c.-775G>A		upstream_gene	N/A	NP_001273289.1	Q8IXY8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD2	ENST00000258052.8	TSL:1 MANE Select	c.59C>T	p.Pro20Leu	missense	Exon 2 of 10	ENSP00000258052.3	O60906
	SMPD2	ENST00000882801.1		c.59C>T	p.Pro20Leu	missense	Exon 2 of 9	ENSP00000552860.1
	SMPD2	ENST00000882802.1		c.51-10C>T		intron	N/A	ENSP00000552861.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250922 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461542 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111750

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.019
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.12
Sift	Benign	0.062	T
Sift4G	Benign	0.16	T
Polyphen		0.12	B
Vest4		0.21
MutPred		0.62		Gain of MoRF binding (P = 0.0438)
MVP		0.58
MPC		0.11
ClinPred		0.63	D
GERP RS		3.9
PromoterAI		-0.030	Neutral
Varity_R		0.17
gMVP		0.75
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758916713; hg19: chr6-109762568;