Genetic Variant CAPSL:p.Thr177Ser (chr5-35904643-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001042625.2(CAPSL):c.529A>T(p.Thr177Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,611,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CAPSL
NM_001042625.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.58

Variant links:

Genes affected

CAPSL (HGNC:28375): (calcyphosine like) Predicted to enable calcium ion binding activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CAPSL links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPSL	NM_001042625.2 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5	ENST00000651391.1	NP_001036090.1	Q8WWF8
CAPSL	NM_144647.4 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5		NP_653248.3	Q8WWF8
CAPSL	XM_006714444.4 link	c.580A>T	p.Thr194Ser	missense_variant	Exon 5 of 5		XP_006714507.1
CAPSL	XM_006714445.4 link	c.*53A>T		3_prime_UTR_variant	Exon 5 of 5		XP_006714508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPSL	ENST00000651391.1 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5		NM_001042625.2	ENSP00000498465.1	Q8WWF8
CAPSL	ENST00000397367.6 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5	1		ENSP00000380524.2	Q8WWF8
CAPSL	ENST00000397366.5 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5	3		ENSP00000380523.1	Q8WWF8
CAPSL	ENST00000513623.5 link	c.529A>T	p.Thr177Ser	missense_variant	Exon 5 of 5	3		ENSP00000424806.1	D6RF97

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

239086

Hom.:

AF XY:

0.000100

AC XY:

AN XY:

129424

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.0000312

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

315

AN:

1459698

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

726074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000266

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151764

Hom.:

Cov.:

AF XY:

0.0000945

AC XY:

AN XY:

74086

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000299

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529A>T (p.T177S) alteration is located in exon 5 (coding exon 4) of the CAPSL gene. This alteration results from a A to T substitution at nucleotide position 529, causing the threonine (T) at amino acid position 177 to be replaced by a serine (S). 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

0.21

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

.;T;T

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.049

D;D;D

Polyphen

0.0020

B;B;.

Vest4

0.83

MutPred

0.51

Loss of catalytic residue at M182 (P = 0.0339);Loss of catalytic residue at M182 (P = 0.0339);Loss of catalytic residue at M182 (P = 0.0339);

MVP

0.53

MPC

0.025

ClinPred

0.21

GERP RS

6.0

Varity_R

0.47

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over