18-24156379-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000621648.4(CABYR):ā€‹c.878T>Cā€‹(p.Ile293Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

CABYR
ENST00000621648.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00
Variant links:
Genes affected
CABYR (HGNC:15569): (calcium binding tyrosine phosphorylation regulated) To reach fertilization competence, spermatozoa undergo a series of morphological and molecular maturational processes, termed capacitation, involving protein tyrosine phosphorylation and increased intracellular calcium. The protein encoded by this gene localizes to the principal piece of the sperm flagellum in association with the fibrous sheath and exhibits calcium-binding when phosphorylated during capacitation. A pseudogene on chromosome 3 has been identified for this gene. Alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

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=0.23893547).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CABYRNM_153769.3 linkuse as main transcriptc.541+337T>C intron_variant ENST00000399496.8 NP_722453.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CABYRENST00000399496.8 linkuse as main transcriptc.541+337T>C intron_variant 1 NM_153769.3 ENSP00000382419 P1O75952-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000576
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
249012
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152366
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2023The c.878T>C (p.I293T) alteration is located in exon 4 (coding exon 3) of the CABYR gene. This alteration results from a T to C substitution at nucleotide position 878, causing the isoleucine (I) at amino acid position 293 to be replaced by a threonine (T). 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
Pathogenic
0.77
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.12
T;.;T;T;T
Eigen
Benign
0.15
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.71
T;T;.;.;T
M_CAP
Benign
0.0097
T
MetaRNN
Benign
0.24
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
.;.;M;M;M
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.80
.;.;N;.;.
REVEL
Benign
0.17
Sift
Uncertain
0.0030
.;.;D;.;.
Sift4G
Benign
0.39
T;T;T;T;T
Polyphen
0.99, 0.96
.;D;D;D;D
Vest4
0.50
MVP
0.27
ClinPred
0.55
D
GERP RS
5.7
Varity_R
0.16
gMVP
0.25

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202161167; hg19: chr18-21736343; COSMIC: COSV59110332; COSMIC: COSV59110332; API