chrX-2843067-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003918.3(GYG2):​c.77C>A​(p.Ala26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 541,734 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 hemizygotes in GnomAD. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 4 hem., cov: 22)
Exomes 𝑓: 0.00019 ( 0 hom. 49 hem. )

Consequence

GYG2
NM_003918.3 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.116
Variant links:
Genes affected
GYG2 (HGNC:4700): (glycogenin 2) This gene encodes a member of the the glycogenin family. Glycogenin is a self-glucosylating protein involved in the initiation reactions of glycogen biosynthesis. A gene on chromosome 3 encodes the muscle glycogenin and this X-linked gene encodes the glycogenin mainly present in liver; both are involved in blood glucose homeostasis. This gene has a short version on chromosome Y, which is 3' truncated and can not make a functional protein. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011960328).
BP6
Variant X-2843067-C-A is Benign according to our data. Variant chrX-2843067-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1317898.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GYG2NM_001079855.2 linkc.8-146C>A intron_variant Intron 2 of 10 ENST00000398806.8 NP_001073324.1 O15488-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GYG2ENST00000398806.8 linkc.8-146C>A intron_variant Intron 2 of 10 1 NM_001079855.2 ENSP00000381786.3 O15488-2

Frequencies

GnomAD3 genomes
AF:
0.0000894
AC:
10
AN:
111824
Hom.:
0
Cov.:
22
AF XY:
0.000118
AC XY:
4
AN XY:
34014
show subpopulations
Gnomad AFR
AF:
0.0000975
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00149
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000565
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000213
AC:
24
AN:
112653
Hom.:
0
AF XY:
0.000434
AC XY:
16
AN XY:
36887
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00143
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000901
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000186
AC:
80
AN:
429860
Hom.:
0
Cov.:
6
AF XY:
0.000324
AC XY:
49
AN XY:
151448
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000675
Gnomad4 OTH exome
AF:
0.000126
GnomAD4 genome
AF:
0.0000894
AC:
10
AN:
111874
Hom.:
0
Cov.:
22
AF XY:
0.000117
AC XY:
4
AN XY:
34074
show subpopulations
Gnomad4 AFR
AF:
0.0000973
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00149
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000565
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000113
ExAC
AF:
0.000166
AC:
17

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Oct 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 26 of the GYG2 protein (p.Ala26Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GYG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1317898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 22, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
2.6
DANN
Benign
0.96
DEOGEN2
Benign
0.0026
T;.;.
FATHMM_MKL
Benign
0.0035
N
LIST_S2
Benign
0.60
T;T;T
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.012
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.8
M;M;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.57
N;.;.
REVEL
Benign
0.036
Sift
Uncertain
0.025
D;.;.
Sift4G
Benign
0.27
T;T;.
Polyphen
0.91
P;.;.
Vest4
0.13
MutPred
0.23
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.28
MPC
0.20
ClinPred
0.080
T
GERP RS
0.50
Varity_R
0.41
gMVP
0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs760717128; hg19: chrX-2761108; API