16-55567342-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032330.3(CAPNS2):​c.586C>T​(p.Arg196Trp) 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 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CAPNS2
NM_032330.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11
Variant links:
Genes affected
CAPNS2 (HGNC:16371): (calpain small subunit 2) Enables calcium-dependent cysteine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
LPCAT2 (HGNC:26032): (lysophosphatidylcholine acyltransferase 2) This gene encodes a member of the lysophospholipid acyltransferase family. The encoded enzyme may function in two ways: to catalyze the biosynthesis of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) from 1-O-alkyl-sn-glycero-3-phosphocholine, and to catalyze the synthesis of glycerophospholipid precursors from arachidonyl-CoA and lysophosphatidylcholine. The encoded protein may function in membrane biogenesis and production of platelet-activating factor in inflammatory cells. The enzyme may localize to the endoplasmic reticulum and the Golgi. [provided by RefSeq, Feb 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPNS2NM_032330.3 linkc.586C>T p.Arg196Trp missense_variant Exon 1 of 1 ENST00000457326.3 NP_115706.1
LPCAT2NM_017839.5 linkc.1216-7289C>T intron_variant Intron 11 of 13 ENST00000262134.10 NP_060309.2 Q7L5N7-1
LPCAT2XM_047434277.1 linkc.1048-7289C>T intron_variant Intron 11 of 13 XP_047290233.1
LPCAT2XM_011523169.4 linkc.406-7289C>T intron_variant Intron 8 of 10 XP_011521471.1 Q7L5N7-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPNS2ENST00000457326.3 linkc.586C>T p.Arg196Trp missense_variant Exon 1 of 1 6 NM_032330.3 ENSP00000400882.2 Q96L46
LPCAT2ENST00000262134.10 linkc.1216-7289C>T intron_variant Intron 11 of 13 1 NM_017839.5 ENSP00000262134.5 Q7L5N7-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000163
AC:
4
AN:
245526
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133438
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000364
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461374
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726956
show subpopulations
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000153
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.586C>T (p.R196W) alteration is located in exon 1 (coding exon 1) of the CAPNS2 gene. This alteration results from a C to T substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a tryptophan (W). 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
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.29
T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Benign
0.67
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-7.7
D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.85
Loss of disorder (P = 0.0947);
MVP
0.81
MPC
0.58
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.67
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs775683433; hg19: chr16-55601254; API