Genetic Variant CYLC1:p.Ser196Thr (chrX-83873294-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_021118.3(CYLC1):c.586T>A(p.Ser196Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,200,322 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

CYLC1
NM_021118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.117

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015063524).

BS2

High Hemizygotes in GnomAd4 at 2 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021118.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLC1	NM_021118.3	MANE Select	c.586T>A	p.Ser196Thr	missense	Exon 4 of 5	NP_066941.1	P35663
	CYLC1	NM_001271680.2		c.174+1724T>A		intron	N/A	NP_001258609.1	A0A087WXC8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLC1	ENST00000329312.5	TSL:1 MANE Select	c.586T>A	p.Ser196Thr	missense	Exon 4 of 5	ENSP00000331556.4	P35663
	CYLC1	ENST00000621735.4	TSL:3	c.174+1724T>A		intron	N/A	ENSP00000480907.1	A0A087WXC8

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

110567

Hom.:

Cov.:

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:

0.00114

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000644

AC:

AN:

170881

AF XY:

0.0000338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000825

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1089706

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

357472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25882

American (AMR)

AF:

0.00

AC:

AN:

33754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18946

East Asian (EAS)

AF:

0.000830

AC:

AN:

30103

South Asian (SAS)

AF:

0.0000383

AC:

AN:

52270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40333

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

838692

Other (OTH)

AF:

0.00

AC:

AN:

45663

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000362

AC:

AN:

110616

Hom.:

Cov.:

AF XY:

0.0000603

AC XY:

AN XY:

33156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30599

American (AMR)

AF:

0.00

AC:

AN:

10318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2630

East Asian (EAS)

AF:

0.00114

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5933

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52541

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000743

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.60

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.0033

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.34

M_CAP

Benign

0.0015

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-0.12

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

REVEL

Benign

0.097

Sift

Benign

0.64

Sift4G

Benign

0.56

Polyphen

0.058

Vest4

0.081

MVP

0.15

MPC

0.0029

ClinPred

0.051

GERP RS

-5.1

Varity_R

0.069

gMVP

0.016

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over