Genetic Variant GCNA:p.Ser166Leu (chrX-71603774-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_052957.5(GCNA):c.497C>T(p.Ser166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,207,502 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 2 hem. )

Consequence

GCNA
NM_052957.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.64

Publications

0 publications found

Variant links:

Genes affected

GCNA (HGNC:15805): (germ cell nuclear acidic peptidase) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

GCNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05848849).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052957.5. 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
	GCNA	NM_052957.5	MANE Select	c.497C>T	p.Ser166Leu	missense	Exon 8 of 13	NP_443189.1	Q96QF7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCNA	ENST00000373696.8	TSL:1 MANE Select	c.497C>T	p.Ser166Leu	missense	Exon 8 of 13	ENSP00000362800.3	Q96QF7
GCNA	ENST00000373695.1	TSL:1	c.497C>T	p.Ser166Leu	missense	Exon 7 of 12	ENSP00000362799.1	Q96QF7
GCNA	ENST00000917930.1		c.497C>T	p.Ser166Leu	missense	Exon 8 of 13	ENSP00000587989.1

Frequencies

GnomAD3 genomes

AF:

0.00000910

AC:

AN:

109883

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183402

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097619

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363403

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26328

American (AMR)

AF:

0.00

AC:

AN:

35138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30147

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

841798

Other (OTH)

AF:

0.00

AC:

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.00000910

AC:

AN:

109883

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32367

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29962

American (AMR)

AF:

0.00

AC:

AN:

10388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00

AC:

AN:

2541

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

231

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52664

Other (OTH)

AF:

0.00

AC:

AN:

1483

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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.:

ExAC

AF:

0.00000824

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

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.99

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.010

FATHMM_MKL

Benign

0.016

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.015

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

-1.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.53

REVEL

Benign

0.019

Sift

Benign

0.12

Sift4G

Uncertain

0.014

Polyphen

0.90

Vest4

0.082

MutPred

0.35

Loss of phosphorylation at S166 (P = 4e-04)

MVP

0.043

MPC

0.18

ClinPred

0.098

GERP RS

0.14

Varity_R

0.077

gMVP

0.013

Mutation Taster

=97/3

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