1-26197743-A-C

Variant names:

• chr1-26197743-A-C
• rs2088958269
• NM_198137.2:c.517A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198137.2(CATSPER4):​c.517A>C​(p.Ile173Leu) 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 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. I173F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CATSPER4 NM_198137.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.596
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21866798).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198137.2. 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
	CATSPER4	NM_198137.2	MANE Select	c.517A>C	p.Ile173Leu	missense	Exon 4 of 10	NP_937770.1	Q7RTX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CATSPER4	ENST00000456354.7	TSL:1 MANE Select	c.517A>C	p.Ile173Leu	missense	Exon 4 of 10	ENSP00000390423.3	Q7RTX7-1
	CATSPER4	ENST00000518899.5	TSL:1	n.517A>C		non_coding_transcript_exon	Exon 4 of 10	ENSP00000429464.1	Q7RTX7-2
	CATSPER4	ENST00000338855.6	TSL:5	c.517A>C	p.Ile173Leu	missense	Exon 4 of 9	ENSP00000341006.2	J3KNU1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.033
DANN	Benign	0.86
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.56	N
PhyloP100		-0.60
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.38
Sift	Benign	0.31	T
Sift4G	Benign	0.062	T
Polyphen		0.44	B
Vest4		0.21
MutPred		0.63		Loss of catalytic residue at I173 (P = 0.1951)
MVP		0.61
MPC		0.19
ClinPred		0.22	T
GERP RS		-1.5
Varity_R		0.11
gMVP		0.81
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2088958269; hg19: chr1-26524234;