chr13-23324551-G-A

Variant names:

• chr13-23324551-G-A
• rs139369964
• NM_000231.3:c.*10G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000231.3(SGCG):​c.*10G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,607,146 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SGCG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0073 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: SGCG NM_000231.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -2.85
• Publications: 0 publications found

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]

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

LOC107984585 (HGNC:):

ACMG classification

Specifications for SGCG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-23324551-G-A is Benign according to our data. Variant chr13-23324551-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255599.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00726 (1105/152188) while in subpopulation AFR AF = 0.0251 (1041/41500). AF 95% confidence interval is 0.0238. There are 12 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000231.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	NM_000231.3	MANE Select	c.*10G>A		3_prime_UTR	Exon 8 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.*10G>A		3_prime_UTR	Exon 8 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.*10G>A		3_prime_UTR	Exon 9 of 9	NP_001365174.1	Q13326

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	ENST00000218867.4	TSL:1 MANE Select	c.*10G>A		3_prime_UTR	Exon 8 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.*10G>A		3_prime_UTR	Exon 9 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.*10G>A		3_prime_UTR	Exon 9 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes AF: 0.00727 AC: 1106 AN: 152070 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

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: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00200 AC: 497 AN: 248612 AF XY: 0.00144

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000751 AC: 1092 AN: 1454958 Hom.: 11 Cov.: 33 AF XY: 0.000664 AC XY: 481 AN XY: 723976

African (AFR) AF: 0.0261 AC: 870 AN: 33394

American (AMR) AF: 0.00141 AC: 63 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49074

Middle Eastern (MID) AF: 0.000931 AC: 4 AN: 4298

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111318

Other (OTH) AF: 0.00171 AC: 103 AN: 60194

GnomAD4 genome AF: 0.00726 AC: 1105 AN: 152188 Hom.: 12 Cov.: 32 AF XY: 0.00700 AC XY: 521 AN XY: 74400

African (AFR) AF: 0.0251 AC: 1041 AN: 41500

American (AMR) AF: 0.00340 AC: 52 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00306 Hom.: 3

Bravo AF: 0.00785

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2C (2)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.59
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139369964; hg19: chr13-23898690;