rs797045106

Positions:

• chr13-23203888-CAGTA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Very_Strong

The NM_000231.3(SGCG):​c.195+4_195+7del variant causes a splice donor, splice donor region, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,591,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: SGCG NM_000231.3 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.22146119 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 16, new splice context is: ctgGTaagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-23203888-CAGTA-C is Pathogenic according to our data. Variant chr13-23203888-CAGTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 208611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23203888-CAGTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3	c.195+4_195+7del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	2/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4	c.195+4_195+7del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	2/8	1	NM_000231.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251320 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135856

Gnomad AFR exome AF: 0.0000616

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000368 AC: 53 AN: 1439442 Hom.: 0 AF XY: 0.0000293 AC XY: 21 AN XY: 717648

Gnomad4 AFR exome AF: 0.0000303

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: 0.0000440

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 30, 2014	The c.195+4_195+7del variant in SGCG has been reported in 1 homozygous and 2 compound heterozygous individuals with limb girdle muscular dystrophy type 2C (LGMD2C; Bonnemann 2002). This variant has also been identified in 1/8254 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is a deletion of 4 nucleotides in the 5' splice region and in vitro functional assays suggest that this variant leads to altered splicing and the inclusion of an additional 16 nucleotides (Bonnemann 2002), which is predicted to lead to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for LGMD2C in an autosomal recessive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM ). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change falls in intron 2 of the SGCG gene. It does not directly change the encoded amino acid sequence of the SGCG protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs758531560, gnomAD 0.004%). This variant has been observed in individuals with limb-girdle muscular dystrophy (PMID: 11801399, 17897828, 19770540). This variant is also known as c.195+2_5del. ClinVar contains an entry for this variant (Variation ID: 208611). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in a 16-bp intronic insertion and introduces a premature termination codon (PMID: 11801399). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 23, 2021	The SGCG c.195+4_195+7delAGTA variant (rs797045106), also published as del 4-bp intron 2 or 195+2_5del, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with limb-girdle muscular dystrophy or a sarcoglycanopathy (Bonnemann 2002, Khadilkar 2009, Reddy 2017). This variant is found on only three chromosomes (3/282718 alleles) in the Genome Aggregation Database. This is an intronic variant in that deletes four conserved nucleotides, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with these predictions, RNA studies of patients with this variant demonstrate use of cryptic splice donor site downstream, resulting in a 16 nucleotide insertion that leads to a frameshift (Bonnemann 2002). Based on available information, this variant is considered to be pathogenic. References: Bonnemann et al., Primary gamma-sarcoglycanopathy (LGMD 2C): broadening of the mutational spectrum guided by the immunohistochemical profile. Neuromuscul Disord. 2002 Mar;12(3):273-80. PMID: 11801399. Khadilkar SV et al. Spectrum of mutations in sarcoglycan genes in the Mumbai region of western India: high prevalence of 525del T. Neurol India. 2009 Jul-Aug;57(4):406-10. PMID: 19770540. Reddy et al., The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2017 Feb;62(2):243-252. PMID: 27708273. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: 21
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045106; hg19: chr13-23778027;