Genetic Variant CYLC1:p.Lys129Asn (chrX-83873095-A-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

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

The NM_021118.3(CYLC1):c.387A>C(p.Lys129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,193,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 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 (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 45 hem. )

Consequence

CYLC1
NM_021118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.621

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]

CYLC1 links:

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=0.03601563).

BS2

High Hemizygotes in GnomAd4 at 8 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
CYLC1	NM_021118.3 link	c.387A>C	p.Lys129Asn	missense_variant	Exon 4 of 5	ENST00000329312.5	NP_066941.1	P35663Q6PEK4
CYLC1	XM_005262086.5 link	c.384A>C	p.Lys128Asn	missense_variant	Exon 4 of 5		XP_005262143.1
CYLC1	NM_001271680.2 link	c.174+1525A>C		intron_variant	Intron 3 of 3		NP_001258609.1	A0A087WXC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLC1	ENST00000329312.5 link	c.387A>C	p.Lys129Asn	missense_variant	Exon 4 of 5	1	NM_021118.3	ENSP00000331556.4		P35663
CYLC1	ENST00000621735.4 link	c.174+1525A>C		intron_variant	Intron 3 of 3	3		ENSP00000480907.1		A0A087WXC8

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

111208

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

33614

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:

0.000828

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000209

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000257

AC:

AN:

159251

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

51671

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:

0.000132

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.000261

GnomAD4 exome

AF:

0.000149

AC:

161

AN:

1081846

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

353096

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:

0.00

Gnomad4 FIN exome

AF:

0.000174

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.000110

GnomAD4 genome

AF:

0.000144

AC:

AN:

111208

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

33614

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:

0.000828

Gnomad4 NFE

AF:

0.000209

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000388

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.387A>C (p.K129N) alteration is located in exon 4 (coding exon 4) of the CYLC1 gene. This alteration results from a A to C substitution at nucleotide position 387, causing the lysine (K) at amino acid position 129 to be replaced by an asparagine (N). 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

0.31

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0043

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.48

M_CAP

Benign

0.0070

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

REVEL

Benign

0.039

Sift

Benign

0.039

Sift4G

Benign

0.061

Polyphen

0.61

Vest4

0.13

MutPred

0.42

Loss of methylation at K129 (P = 0.0151);

MVP

0.15

MPC

0.0019

ClinPred

0.064

GERP RS

2.2

Varity_R

0.14

gMVP

0.018

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over