Genetic Variant GCNA:p.Ser28Arg (chrX-71592146-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_052957.5(GCNA):c.84C>G(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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., 0 hem., cov: 20)

Exomes 𝑓: 0.000029 ( 0 hom. 8 hem. )

Failed GnomAD Quality Control

Consequence

GCNA
NM_052957.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0640

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042909354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCNA	NM_052957.5 link	c.84C>G	p.Ser28Arg	missense_variant	Exon 3 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.84C>G	p.Ser28Arg	missense_variant	Exon 3 of 13	1	NM_052957.5	ENSP00000362800.3		Q96QF7
GCNA	ENST00000373695.1 link	c.84C>G	p.Ser28Arg	missense_variant	Exon 2 of 12	1		ENSP00000362799.1		Q96QF7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33336

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000971

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000274

AC:

AN:

182453

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

66929

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000293

AC:

AN:

1093114

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

359012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000286

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000360

AC:

AN:

111148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000971

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000136

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.84C>G (p.S28R) alteration is located in exon 3 (coding exon 2) of the ACRC gene. This alteration results from a C to G substitution at nucleotide position 84, causing the serine (S) at amino acid position 28 to be replaced by an arginine (R). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.4

DANN

Benign

0.85

DEOGEN2

Benign

0.0089

T;T

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.34

.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.013

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.57

T;T

Polyphen

0.0060

B;B

Vest4

0.16

MutPred

0.21

Loss of phosphorylation at S28 (P = 0.0283);Loss of phosphorylation at S28 (P = 0.0283);

MVP

0.043

MPC

0.65

ClinPred

0.11

GERP RS

0.23

Varity_R

0.17

gMVP

0.045

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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