Genetic Variant GCNA:p.Pro14Ser (chrX-71580861-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_052957.5(GCNA):c.40C>T(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,199,462 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 0.00035 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 5 hem. )

Consequence

GCNA
NM_052957.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.497

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017872244).

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCNA	NM_052957.5 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 2 of 13	ENST00000373696.8	NP_443189.1	Q96QF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCNA	ENST00000373696.8 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 2 of 13	1	NM_052957.5	ENSP00000362800.3		Q96QF7
GCNA	ENST00000373695.1 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 12	1		ENSP00000362799.1		Q96QF7

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

112174

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34368

show subpopulations

Gnomad AFR

AF:

0.00123

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:

0.00

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.0000499

AC:

AN:

160368

Hom.:

AF XY:

0.0000397

AC XY:

AN XY:

50382

show subpopulations

Gnomad AFR exome

AF:

0.000697

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1087288

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

355122

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

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:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000348

AC:

AN:

112174

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34368

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.0000373

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40C>T (p.P14S) alteration is located in exon 2 (coding exon 1) of the ACRC gene. This alteration results from a C to T substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 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

Benign

0.093

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.2

DANN

Benign

0.93

DEOGEN2

Benign

0.011

T;T

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.37

.;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.030

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.38

T;T

Polyphen

0.11

B;B

Vest4

0.11

MVP

0.082

MPC

0.68

ClinPred

0.11

GERP RS

-0.63

Varity_R

0.067

gMVP

0.14

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