Variant 5-35910413-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001042625.2(CAPSL):c.268G>T(p.Asp90Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,876 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CAPSL
NM_001042625.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity CAPSL_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPSL	NM_001042625.2 linkuse as main transcript	c.268G>T	p.Asp90Tyr	missense_variant	3/5	ENST00000651391.1	NP_001036090.1	Q8WWF8
CAPSL	NM_144647.4 linkuse as main transcript	c.268G>T	p.Asp90Tyr	missense_variant	3/5		NP_653248.3	Q8WWF8
CAPSL	XM_006714444.4 linkuse as main transcript	c.319G>T	p.Asp107Tyr	missense_variant	3/5		XP_006714507.1
CAPSL	XM_006714445.4 linkuse as main transcript	c.319G>T	p.Asp107Tyr	missense_variant	3/5		XP_006714508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPSL	ENST00000651391.1 linkuse as main transcript	c.268G>T	p.Asp90Tyr	missense_variant	3/5		NM_001042625.2	ENSP00000498465.1		Q8WWF8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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

Bravo

AF:

0.0000302

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 submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.268G>T (p.D90Y) alteration is located in exon 3 (coding exon 2) of the CAPSL gene. This alteration results from a G to T substitution at nucleotide position 268, causing the aspartic acid (D) at amino acid position 90 to be replaced by a tyrosine (Y). 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

0.70

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.5

H;H;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.7

D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.98

D;D;.;.

Vest4

0.80

MutPred

0.79

Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);

MVP

0.97

MPC

0.15

ClinPred

1.0

GERP RS

5.4

Varity_R

0.97

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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