1-26191290-G-A

Position:

• chr1-26191290-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_198137.2(CATSPER4):​c.217G>A​(p.Ala73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,066 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: CATSPER4 NM_198137.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.752

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051654488).
• BP6: Variant 1-26191290-G-A is Benign according to our data. Variant chr1-26191290-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2561316.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CATSPER4	NM_198137.2	c.217G>A	p.Ala73Thr	missense_variant	2/10	ENST00000456354.7	NP_937770.1
CATSPER4	XM_011541432.4	c.217G>A	p.Ala73Thr	missense_variant	2/9		XP_011539734.1
CATSPER4	XM_011541433.3	c.217G>A	p.Ala73Thr	missense_variant	2/7		XP_011539735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CATSPER4	ENST00000456354.7	c.217G>A	p.Ala73Thr	missense_variant	2/10	1	NM_198137.2	ENSP00000390423	P1
CATSPER4	ENST00000518899.5	c.217G>A	p.Ala73Thr	missense_variant, NMD_transcript_variant	2/10	1		ENSP00000429464
CATSPER4	ENST00000338855.6	c.217G>A	p.Ala73Thr	missense_variant	2/9	5		ENSP00000341006

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251114 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135776

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461798 Hom.: 1 Cov.: 35 AF XY: 0.0000853 AC XY: 62 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000189 AC: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.060	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.98	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.45	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0040	.;B
Vest4		0.035
MutPred		0.32		Loss of catalytic residue at A73 (P = 0.0016);Loss of catalytic residue at A73 (P = 0.0016);
MVP		0.54
MPC		0.17
ClinPred		0.0030	T
GERP RS		2.6
Varity_R		0.036
gMVP		0.28

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: rs778169515; hg19: chr1-26517781;