X-83873283-C-T

Variant names:

• chrX-83873283-C-T
• rs753206308
• NM_021118.3:c.575C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_021118.3(CYLC1):​c.575C>T​(p.Ser192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,089,159 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: CYLC1 NM_021118.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062182248).
• BS2: High Hemizygotes in GnomAdExome4 at 2 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	c.575C>T	p.Ser192Leu	missense_variant	Exon 4 of 5	ENST00000329312.5	NP_066941.1
CYLC1	XM_005262086.5	c.572C>T	p.Ser191Leu	missense_variant	Exon 4 of 5		XP_005262143.1
CYLC1	NM_001271680.2	c.174+1713C>T		intron_variant	Intron 3 of 3		NP_001258609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLC1	ENST00000329312.5	c.575C>T	p.Ser192Leu	missense_variant	Exon 4 of 5	1	NM_021118.3	ENSP00000331556.4
CYLC1	ENST00000621735.4	c.174+1713C>T		intron_variant	Intron 3 of 3	3		ENSP00000480907.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000587 AC: 1 AN: 170486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 58990

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: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 7 AN: 1089159 Hom.: 0 Cov.: 30 AF XY: 0.00000560 AC XY: 2 AN XY: 357001

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: 0.00

Gnomad4 NFE exome AF: 0.00000835

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575C>T (p.S192L) 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 575, causing the serine (S) at amino acid position 192 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	-0.52	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.61
DEOGEN2	Benign	0.0054	T
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.038
Sift	Benign	1.0	T
Sift4G	Benign	0.25	T
Polyphen		0.11	B
Vest4		0.069
MutPred		0.31		Gain of helix (P = 0.0078);
MVP		0.043
MPC		0.0038
ClinPred		0.051	T
GERP RS		-0.25
Varity_R		0.059
gMVP		0.027

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: rs753206308; hg19: chrX-83128291;