16-55567130-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032330.3(CAPNS2):c.374G>A(p.Arg125Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,756 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: CAPNS2 NM_032330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24141353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPNS2	NM_032330.3	c.374G>A	p.Arg125Gln	missense_variant	1/1	ENST00000457326.3
LPCAT2	NM_017839.5	c.1216-7501G>A		intron_variant		ENST00000262134.10
LPCAT2	XM_011523169.4	c.406-7501G>A		intron_variant
LPCAT2	XM_047434277.1	c.1048-7501G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPNS2	ENST00000457326.3	c.374G>A	p.Arg125Gln	missense_variant	1/1		NM_032330.3	P1
LPCAT2	ENST00000262134.10	c.1216-7501G>A		intron_variant		1	NM_017839.5	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00117 AC: 291 AN: 248884 Hom.: 0 AF XY: 0.00124 AC XY: 168 AN XY: 134996

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00154 AC: 2258 AN: 1461552 Hom.: 3 Cov.: 31 AF XY: 0.00154 AC XY: 1117 AN XY: 727054

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74416

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000764 AC: 3

ESP6500EA AF: 0.00227 AC: 19

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00225

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 18, 2021

The c.374G>A (p.R125Q) alteration is located in exon 1 (coding exon 1) of the CAPNS2 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a glutamine (Q). 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	0.29
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.087	T
Polyphen		1.0	D
Vest4		0.93
MVP		0.93
MPC		0.56
ClinPred		0.037	T
GERP RS		6.0
Varity_R		0.59
gMVP		0.21

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: rs146637108; hg19: chr16-55601042;