6-109442994-C-A

Variant names:

• chr6-109442994-C-A
• rs1775008233
• NM_003080.3:c.642C>A

Variant summary

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

The NM_003080.3(SMPD2):​c.642C>A​(p.Asn214Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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: 6.8e-7 (0 hom.)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.308

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]

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=0.13059643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD2	NM_003080.3	c.642C>A	p.Asn214Lys	missense_variant	Exon 8 of 10	ENST00000258052.8	NP_003071.2
SMPD2	XM_011536079.2	c.327C>A	p.Asn109Lys	missense_variant	Exon 6 of 8		XP_011534381.1
SMPD2	XR_942566.3	n.1040C>A		non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD2	ENST00000258052.8	c.642C>A	p.Asn214Lys	missense_variant	Exon 8 of 10	1	NM_003080.3	ENSP00000258052.3
SMPD2	ENST00000458487.1	c.330C>A	p.Asn110Lys	missense_variant	Exon 2 of 4	2		ENSP00000399731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.642C>A (p.N214K) alteration is located in exon 8 (coding exon 8) of the SMPD2 gene. This alteration results from a C to A substitution at nucleotide position 642, causing the asparagine (N) at amino acid position 214 to be replaced by a lysine (K). 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	0.18
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.1
DANN	Benign	0.68
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.24
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0050	B
Vest4		0.19
MutPred		0.60		Gain of methylation at N214 (P = 0.0074);
MVP		0.60
MPC		0.086
ClinPred		0.30	T
GERP RS		-4.6
Varity_R		0.23
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1775008233; hg19: chr6-109764197;