6-109443020-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003080.3(SMPD2):ā€‹c.668T>Cā€‹(p.Val223Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V223I) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

SMPD2
NM_003080.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07178897).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMPD2NM_003080.3 linkuse as main transcriptc.668T>C p.Val223Ala missense_variant 8/10 ENST00000258052.8 NP_003071.2 O60906
SMPD2XM_011536079.2 linkuse as main transcriptc.353T>C p.Val118Ala missense_variant 6/8 XP_011534381.1
SMPD2XR_942566.3 linkuse as main transcriptn.1066T>C non_coding_transcript_exon_variant 8/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMPD2ENST00000258052.8 linkuse as main transcriptc.668T>C p.Val223Ala missense_variant 8/101 NM_003080.3 ENSP00000258052.3 O60906
SMPD2ENST00000458487.1 linkuse as main transcriptc.356T>C p.Val119Ala missense_variant 2/42 ENSP00000399731.1 H0Y5N2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251336
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461878
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.0000805
AC XY:
6
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2023The c.668T>C (p.V223A) alteration is located in exon 8 (coding exon 8) of the SMPD2 gene. This alteration results from a T to C substitution at nucleotide position 668, causing the valine (V) at amino acid position 223 to be replaced by an alanine (A). 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
0.23
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.21
T
Eigen
Benign
0.10
Eigen_PC
Benign
0.19
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.072
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.46
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.16
N
REVEL
Benign
0.21
Sift
Benign
0.16
T
Sift4G
Benign
0.33
T
Polyphen
1.0
D
Vest4
0.13
MVP
0.65
MPC
0.10
ClinPred
0.084
T
GERP RS
6.0
Varity_R
0.075
gMVP
0.54

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs531649765; hg19: chr6-109764223; API