6-109443023-G-C

Position:

• chr6-109443023-G-C

Variant summary

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

The NM_003080.3(SMPD2):​c.671G>C​(p.Ser224Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0680

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]

SMPD2 (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=0.073982954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD2	NM_003080.3	c.671G>C	p.Ser224Thr	missense_variant	8/10	ENST00000258052.8	NP_003071.2
SMPD2	XM_011536079.2	c.356G>C	p.Ser119Thr	missense_variant	6/8		XP_011534381.1
SMPD2	XR_942566.3	n.1069G>C		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD2	ENST00000258052.8	c.671G>C	p.Ser224Thr	missense_variant	8/10	1	NM_003080.3	ENSP00000258052.3
SMPD2	ENST00000458487.1	c.359G>C	p.Ser120Thr	missense_variant	2/4	2		ENSP00000399731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.671G>C (p.S224T) alteration is located in exon 8 (coding exon 8) of the SMPD2 gene. This alteration results from a G to C substitution at nucleotide position 671, causing the serine (S) at amino acid position 224 to be replaced by a threonine (T). 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	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.6
DANN	Benign	0.62
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.20
Sift	Benign	0.50	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.43		Gain of phosphorylation at S224 (P = 0.0684);
MVP		0.40
MPC		0.071
ClinPred		0.043	T
GERP RS		-3.3
Varity_R		0.081
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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: chr6-109764226;