1-26190752-C-T

Variant names:

• chr1-26190752-C-T
• rs144361455
• NM_198137.2:c.125C>T

Variant summary

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

The NM_198137.2(CATSPER4):​c.125C>T​(p.Pro42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,324 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CATSPER4 NM_198137.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.584

Genes affected

CATSPER4 (HGNC:23220): (cation channel sperm associated 4) 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 and sperm principal piece. [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=0.11504704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CATSPER4	NM_198137.2	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 10	ENST00000456354.7	NP_937770.1
CATSPER4	XM_011541432.4	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 9		XP_011539734.1
CATSPER4	XM_011541433.3	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 7		XP_011539735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CATSPER4	ENST00000456354.7	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 10	1	NM_198137.2	ENSP00000390423.3
CATSPER4	ENST00000518899.5	n.125C>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000429464.1
CATSPER4	ENST00000338855.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 9	5		ENSP00000341006.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249328 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135074

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726904

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.21	N;N
REVEL	Benign	0.096
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.063	.;B
Vest4		0.19
MutPred		0.38		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.55
MPC		0.18
ClinPred		0.074	T
GERP RS		2.4
Varity_R		0.023
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs144361455; hg19: chr1-26517243;