Genetic Variant CYLC1:p.Gln155Glu (chrX-83873171-C-G) – 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.463C>G(p.Gln155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,202,492 control chromosomes in the GnomAD database, including 2 homozygotes. There are 126 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 0.00026 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00032 ( 2 hom. 121 hem. )

Consequence

CYLC1
NM_021118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.42

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=0.009558111).

BS2

High Hemizygotes in GnomAd4 at 5 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.463C>G	p.Gln155Glu	missense_variant	Exon 4 of 5	ENST00000329312.5	NP_066941.1	P35663Q6PEK4
CYLC1	XM_005262086.5 link	c.460C>G	p.Gln154Glu	missense_variant	Exon 4 of 5		XP_005262143.1
CYLC1	NM_001271680.2 link	c.174+1601C>G		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.463C>G	p.Gln155Glu	missense_variant	Exon 4 of 5	1	NM_021118.3	ENSP00000331556.4		P35663
CYLC1	ENST00000621735.4 link	c.174+1601C>G		intron_variant	Intron 3 of 3	3		ENSP00000480907.1		A0A087WXC8

Frequencies

GnomAD3 genomes

AF:

0.000261

AC:

AN:

110926

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33416

show subpopulations

Gnomad AFR

AF:

0.0000979

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000579

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000666

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.000285

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000492

AC:

AN:

172907

Hom.:

AF XY:

0.000432

AC XY:

AN XY:

60229

show subpopulations

Gnomad AFR exome

AF:

0.0000821

Gnomad AMR exome

AF:

0.00137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000175

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000390

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.000324

AC:

354

AN:

1091512

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

121

AN XY:

358196

show subpopulations

Gnomad4 AFR exome

AF:

0.000575

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.0000522

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000227

Gnomad4 FIN exome

AF:

0.000322

Gnomad4 NFE exome

AF:

0.000240

Gnomad4 OTH exome

AF:

0.000896

GnomAD4 genome

AF:

0.000261

AC:

AN:

110980

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33480

show subpopulations

Gnomad4 AFR

AF:

0.0000977

Gnomad4 AMR

AF:

0.000578

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000666

Gnomad4 NFE

AF:

0.000285

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000567

ExAC

AF:

0.000603

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.463C>G (p.Q155E) alteration is located in exon 4 (coding exon 4) of the CYLC1 gene. This alteration results from a C to G substitution at nucleotide position 463, causing the glutamine (Q) at amino acid position 155 to be replaced by a glutamic acid (E). 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

0.080

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0080

DANN

Benign

0.089

DEOGEN2

Benign

0.0025

FATHMM_MKL

Benign

0.0050

LIST_S2

Benign

0.46

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.24

PROVEAN

Benign

0.29

REVEL

Benign

0.031

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.12

Vest4

0.026

MVP

0.18

MPC

0.0021

ClinPred

0.0032

GERP RS

-9.3

Varity_R

0.047

gMVP

0.0074

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