5-134968004-C-T

Variant names:

• chr5-134968004-C-T
• rs140980095
• NM_178019.3:c.13C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178019.3(CATSPER3):​c.13C>T​(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,662 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (1 hom.)
• Consequence: CATSPER3 NM_178019.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

Genes affected

CATSPER3 (HGNC:20819): (cation channel sperm associated 3) Predicted to enable voltage-gated calcium channel activity. Predicted to be involved in flagellated sperm motility; sodium ion transport; and sperm capacitation. Predicted to be located in plasma membrane. Predicted to be part of CatSper complex. Predicted to be active in acrosomal vesicle. [provided by Alliance of Genome Resources, Apr 2022]

PCBD2 (HGNC:24474): (pterin-4 alpha-carbinolamine dehydratase 2) Predicted to enable 4-alpha-hydroxytetrahydrobiopterin dehydratase activity. Involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016904056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CATSPER3	NM_178019.3	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 8	ENST00000282611.8	NP_821138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CATSPER3	ENST00000282611.8	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 8	1	NM_178019.3	ENSP00000282611.6
PCBD2	ENST00000512783.5	c.*3552C>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000421544.1
CATSPER3	ENST00000511235.1	n.98C>T		non_coding_transcript_exon_variant	Exon 1 of 3	4
PCBD2	ENST00000504352.1	n.*18-1935C>T		intron_variant	Intron 4 of 7	5		ENSP00000426161.1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251398 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135866

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1461432 Hom.: 1 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 727044

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000179

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: 0.0000171

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74422

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000681 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13C>T (p.R5C) alteration is located in exon 1 (coding exon 1) of the CATSPER3 gene. This alteration results from a C to T substitution at nucleotide position 13, causing the arginine (R) at amino acid position 5 to be replaced by a cysteine (C). 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	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.8
DANN	Benign	0.86
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.92	P
Vest4		0.12
MVP		0.41
MPC		0.19
ClinPred		0.023	T
GERP RS		-5.4
Varity_R		0.041
gMVP		0.27

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

Other links and lift over

dbSNP: rs140980095; hg19: chr5-134303694;