Genetic Variant CYLC1:p.Lys274Asn (chrX-83873530-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_021118.3(CYLC1):c.822G>T(p.Lys274Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,196,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts 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. K274E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 7 hem. )

Consequence

CYLC1
NM_021118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.72

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34235907).

BS2

High Hemizygotes in GnomAdExome4 at 7 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.822G>T	p.Lys274Asn	missense_variant	Exon 4 of 5	ENST00000329312.5	NP_066941.1	P35663Q6PEK4
CYLC1	XM_005262086.5 link	c.819G>T	p.Lys273Asn	missense_variant	Exon 4 of 5		XP_005262143.1
CYLC1	NM_001271680.2 link	c.174+1960G>T		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.822G>T	p.Lys274Asn	missense_variant	Exon 4 of 5	1	NM_021118.3	ENSP00000331556.4		P35663
CYLC1	ENST00000621735.4 link	c.174+1960G>T		intron_variant	Intron 3 of 3	3		ENSP00000480907.1		A0A087WXC8

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

109966

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32512

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:

0.000287

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000230

AC:

AN:

173822

Hom.:

AF XY:

0.00

AC XY:

AN XY:

60974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000741

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1086792

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

354080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000385

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000665

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000204

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000182

AC:

AN:

109966

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000287

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000191

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.822G>T (p.K274N) alteration is located in exon 4 (coding exon 4) of the CYLC1 gene. This alteration results from a G to T substitution at nucleotide position 822, causing the lysine (K) at amino acid position 274 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

Pathogenic

0.63

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.31

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.082

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.43

MutPred

0.39

Loss of methylation at K274 (P = 0.0143);

MVP

0.44

MPC

0.0018

ClinPred

0.67

GERP RS

3.0

Varity_R

0.48

gMVP

0.039

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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