X-83873406-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_021118.3(CYLC1):​c.698C>T​(p.Pro233Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,201,705 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P233S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 3 hem., cov: 22)
Exomes 𝑓: 0.00010 ( 0 hom. 42 hem. )

Consequence

CYLC1
NM_021118.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.17
Variant links:
Genes affected
CYLC1 (HGNC:2582): (cylicin 1) This gene encodes a sperm head cytoskeletal protein. The encoded protein is associated with the calyx of spermatozoa and spermatids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02347666).
BS2
High Hemizygotes in GnomAd4 at 3 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYLC1NM_021118.3 linkc.698C>T p.Pro233Leu missense_variant Exon 4 of 5 ENST00000329312.5 NP_066941.1 P35663Q6PEK4
CYLC1XM_005262086.5 linkc.695C>T p.Pro232Leu missense_variant Exon 4 of 5 XP_005262143.1
CYLC1NM_001271680.2 linkc.174+1836C>T intron_variant Intron 3 of 3 NP_001258609.1 A0A087WXC8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYLC1ENST00000329312.5 linkc.698C>T p.Pro233Leu missense_variant Exon 4 of 5 1 NM_021118.3 ENSP00000331556.4 P35663
CYLC1ENST00000621735.4 linkc.174+1836C>T intron_variant Intron 3 of 3 3 ENSP00000480907.1 A0A087WXC8

Frequencies

GnomAD3 genomes
AF:
0.0000271
AC:
3
AN:
110607
Hom.:
0
Cov.:
22
AF XY:
0.0000904
AC XY:
3
AN XY:
33181
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000571
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000686
AC:
12
AN:
174803
Hom.:
0
AF XY:
0.0000820
AC XY:
5
AN XY:
60969
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000128
Gnomad OTH exome
AF:
0.000467
GnomAD4 exome
AF:
0.000102
AC:
111
AN:
1091098
Hom.:
0
Cov.:
30
AF XY:
0.000117
AC XY:
42
AN XY:
357742
show subpopulations
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:
0.000152
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000120
Gnomad4 OTH exome
AF:
0.0000437
GnomAD4 genome
AF:
0.0000271
AC:
3
AN:
110607
Hom.:
0
Cov.:
22
AF XY:
0.0000904
AC XY:
3
AN XY:
33181
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000571
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000346
AC:
1
ExAC
AF:
0.000107
AC:
13

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.698C>T (p.P233L) alteration is located in exon 4 (coding exon 4) of the CYLC1 gene. This alteration results from a C to T substitution at nucleotide position 698, causing the proline (P) at amino acid position 233 to be replaced by a leucine (L). 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
0.11
BayesDel_addAF
Benign
-0.74
T
BayesDel_noAF
Benign
-1.1
CADD
Benign
0.015
DANN
Benign
0.31
DEOGEN2
Benign
0.0028
T
FATHMM_MKL
Benign
0.0045
N
LIST_S2
Benign
0.43
T
M_CAP
Benign
0.0020
T
MetaRNN
Benign
0.023
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.29
N
REVEL
Benign
0.010
Sift
Benign
0.40
T
Sift4G
Benign
0.26
T
Polyphen
0.0
B
Vest4
0.024
MutPred
0.21
Loss of methylation at K228 (P = 0.0492);
MVP
0.043
MPC
0.0020
ClinPred
0.033
T
GERP RS
-5.5
Varity_R
0.023
gMVP
0.012

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: rs745675150; hg19: chrX-83128414; API