rs1424175093

Variant names:

• chr5-35910456-C-T
• rs1424175093
• NM_001042625.2:c.225G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/24 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.841
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042625.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPSL	NM_001042625.2	MANE Select	c.225G>A	p.Met75Ile	missense	Exon 3 of 5	NP_001036090.1	Q8WWF8
	CAPSL	NM_144647.4		c.225G>A	p.Met75Ile	missense	Exon 3 of 5	NP_653248.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPSL	ENST00000651391.1	MANE Select	c.225G>A	p.Met75Ile	missense	Exon 3 of 5	ENSP00000498465.1	Q8WWF8
	CAPSL	ENST00000397367.6	TSL:1	c.225G>A	p.Met75Ile	missense	Exon 3 of 5	ENSP00000380524.2	Q8WWF8
	CAPSL	ENST00000397366.5	TSL:3	c.225G>A	p.Met75Ile	missense	Exon 3 of 5	ENSP00000380523.1	Q8WWF8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727044

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111556

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	N
PhyloP100		0.84
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.15
Sift	Benign	0.25	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.40		Loss of ubiquitination at K77 (P = 0.0516)
MVP		0.61
MPC		0.019
ClinPred		0.37	T
GERP RS		4.3
Varity_R		0.24
gMVP		0.54
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1424175093; hg19: chr5-35910558; COSMIC: COSV105337716;