13-23279452-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000231.3(SGCG):ā€‹c.479T>Cā€‹(p.Val160Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000663 in 1,613,356 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00039 ( 1 hom., cov: 32)
Exomes š‘“: 0.00069 ( 20 hom. )

Consequence

SGCG
NM_000231.3 missense

Scores

3
10
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.47
Variant links:
Genes affected
SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a chain Gamma-sarcoglycan (size 290) in uniprot entity SGCG_HUMAN there are 28 pathogenic changes around while only 1 benign (97%) in NM_000231.3
BP4
Computational evidence support a benign effect (MetaRNN=0.02032563).
BP6
Variant 13-23279452-T-C is Benign according to our data. Variant chr13-23279452-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311480.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000387 (59/152268) while in subpopulation SAS AF= 0.0116 (56/4824). AF 95% confidence interval is 0.00918. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SGCGNM_000231.3 linkuse as main transcriptc.479T>C p.Val160Ala missense_variant 5/8 ENST00000218867.4 NP_000222.2 Q13326

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SGCGENST00000218867.4 linkuse as main transcriptc.479T>C p.Val160Ala missense_variant 5/81 NM_000231.3 ENSP00000218867.3 Q13326

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152150
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0114
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00141
AC:
355
AN:
251256
Hom.:
7
AF XY:
0.00181
AC XY:
246
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0114
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000691
AC:
1010
AN:
1461088
Hom.:
20
Cov.:
31
AF XY:
0.000989
AC XY:
719
AN XY:
726826
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0110
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.000387
AC:
59
AN:
152268
Hom.:
1
Cov.:
32
AF XY:
0.000524
AC XY:
39
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0116
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000471
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.00147
AC:
178
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Apr 19, 2020- -
Limb-girdle muscular dystrophy, recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Sarcoglycanopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
SGCG-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 27, 2024This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D
MetaRNN
Benign
0.020
T
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.4
D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.89
P
Vest4
0.71
MutPred
0.72
Loss of stability (P = 0.0602);
MVP
0.99
MPC
0.36
ClinPred
0.16
T
GERP RS
5.4
Varity_R
0.65
gMVP
0.49

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: rs527562042; hg19: chr13-23853591; COSMIC: COSV54563023; API