Variant 5-35910456-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001042625.2(CAPSL):c.225G>A(p.Met75Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CAPSL
NM_001042625.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.841

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:

Genome browser will be placed here

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/exons	MANE	Protein	UniProt
CAPSL	NM_001042625.2 linkuse as main transcript	c.225G>A	p.Met75Ile	missense_variant	3/5	ENST00000651391.1	NP_001036090.1	Q8WWF8
CAPSL	NM_144647.4 linkuse as main transcript	c.225G>A	p.Met75Ile	missense_variant	3/5		NP_653248.3	Q8WWF8
CAPSL	XM_006714444.4 linkuse as main transcript	c.276G>A	p.Met92Ile	missense_variant	3/5		XP_006714507.1
CAPSL	XM_006714445.4 linkuse as main transcript	c.276G>A	p.Met92Ile	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.225G>A	p.Met75Ile	missense_variant	3/5		NM_001042625.2	ENSP00000498465.1		Q8WWF8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727044

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Aug 16, 2022

The c.225G>A (p.M75I) alteration is located in exon 3 (coding exon 2) of the CAPSL gene. This alteration results from a G to A substitution at nucleotide position 225, causing the methionine (M) at amino acid position 75 to be replaced by an isoleucine (I). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.052

T;T;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

.;T;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.58

N;N;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.040

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.25

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.18

MutPred

0.40

Loss of ubiquitination at K77 (P = 0.0516);Loss of ubiquitination at K77 (P = 0.0516);Loss of ubiquitination at K77 (P = 0.0516);Loss of ubiquitination at K77 (P = 0.0516);

MVP

0.61

MPC

0.019

ClinPred

0.37

GERP RS

4.3

Varity_R

0.24

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: -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