9-103004734-C-T

Position:

• chr9-103004734-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001340.5(CYLC2):​c.220C>T​(p.Pro74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CYLC2 NM_001340.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

CYLC2 (HGNC:2583): (cylicin 2) Cylicin II (CYCL2) is specifically expressed in testis and is part of the cytoskeletal calyx of mammalian sperm heads. Cylicin II may play a role in the morphogenesis of the sperm head. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYLC2	NM_001340.5	c.220C>T	p.Pro74Ser	missense_variant	4/8	ENST00000374798.8	NP_001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYLC2	ENST00000374798.8	c.220C>T	p.Pro74Ser	missense_variant	4/8	1	NM_001340.5	ENSP00000420256	P1
CYLC2	ENST00000612124.4	c.220C>T	p.Pro74Ser	missense_variant	4/5	1		ENSP00000478399	P1
CYLC2	ENST00000487798.5	c.220C>T	p.Pro74Ser	missense_variant	4/7	5		ENSP00000417674	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453172 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722812

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.220C>T (p.P74S) alteration is located in exon 4 (coding exon 4) of the CYLC2 gene. This alteration results from a C to T substitution at nucleotide position 220, causing the proline (P) at amino acid position 74 to be replaced by a serine (S). 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	0.79
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.58	T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.59	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	.;D;D
REVEL	Benign	0.17
Sift	Benign	0.030	.;D;D
Sift4G	Uncertain	0.057	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.57
MutPred		0.39		Gain of phosphorylation at P74 (P = 0.0064);Gain of phosphorylation at P74 (P = 0.0064);Gain of phosphorylation at P74 (P = 0.0064);
MVP		0.54
MPC		0.0071
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-105767016;