5-35921117-C-A

Position:

• chr5-35921117-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042625.2(CAPSL):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAPSL NM_001042625.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09694463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPSL	NM_001042625.2	c.4G>T	p.Ala2Ser	missense_variant	2/5	ENST00000651391.1
CAPSL	NM_144647.4	c.4G>T	p.Ala2Ser	missense_variant	2/5
CAPSL	XM_006714444.4	c.55G>T	p.Ala19Ser	missense_variant	2/5
CAPSL	XM_006714445.4	c.55G>T	p.Ala19Ser	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPSL	ENST00000651391.1	c.4G>T	p.Ala2Ser	missense_variant	2/5		NM_001042625.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461408 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727028

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 19, 2022

The c.4G>T (p.A2S) alteration is located in exon 2 (coding exon 1) of the CAPSL gene. This alteration results from a G to T substitution at nucleotide position 4, causing the alanine (A) at amino acid position 2 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	0.16
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.029	T;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.69	.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.82	L;L;.;.
MutationTaster	Benign	0.66	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.77	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.0040	B;B;.;.
Vest4		0.28
MutPred		0.11		Gain of glycosylation at A2 (P = 0.0201);Gain of glycosylation at A2 (P = 0.0201);Gain of glycosylation at A2 (P = 0.0201);Gain of glycosylation at A2 (P = 0.0201);
MVP		0.66
MPC		0.018
ClinPred		0.049	T
GERP RS		0.32
Varity_R		0.053
gMVP		0.56

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: rs1479892478; hg19: chr5-35921219;