NM_000231.3:c.579-22G>T

Variant names:

• chr13-23320615-G-T
• rs111358030
• NM_000231.3:c.579-22G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000231.3(SGCG):​c.579-22G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (12 hom., cov: 0)
  • Exomes 𝑓: 0.063 (1291 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCG NM_000231.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.375
• Publications: 3 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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

LOC107984585 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-23320615-G-T is Benign according to our data. Variant chr13-23320615-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 1291 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCG	NM_000231.3	c.579-22G>T		intron_variant	Intron 6 of 7	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.579-22G>T		intron_variant	Intron 6 of 7	1	NM_000231.3	ENSP00000218867.3
SACS	ENST00000682775.1	c.2186-8500C>A		intron_variant	Intron 9 of 9			ENSP00000508399.1
SACS	ENST00000683210.1	c.2186-31372C>A		intron_variant	Intron 9 of 9			ENSP00000506739.1
SACS	ENST00000684325.1	n.*104+951C>A		intron_variant	Intron 10 of 10			ENSP00000508121.1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 1041 AN: 47416 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00463

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0131

GnomAD2 exomes AF: 0.136 AC: 13558 AN: 99330 AF XY: 0.143

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.0889

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.0754

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0628 AC: 40498 AN: 645318 Hom.: 1291 Cov.: 17 AF XY: 0.0642 AC XY: 20422 AN XY: 318308

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0421 AC: 543 AN: 12884

American (AMR) AF: 0.118 AC: 1783 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 1476 AN: 9862

East Asian (EAS) AF: 0.0685 AC: 969 AN: 14144

South Asian (SAS) AF: 0.120 AC: 4018 AN: 33566

European-Finnish (FIN) AF: 0.111 AC: 2467 AN: 22196

Middle Eastern (MID) AF: 0.0883 AC: 181 AN: 2050

European-Non Finnish (NFE) AF: 0.0538 AC: 27427 AN: 509470

Other (OTH) AF: 0.0628 AC: 1634 AN: 26020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0221 AC: 1048 AN: 47470 Hom.: 12 Cov.: 0 AF XY: 0.0232 AC XY: 542 AN XY: 23386

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0274 AC: 316 AN: 11516

American (AMR) AF: 0.0187 AC: 86 AN: 4602

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 18 AN: 832

East Asian (EAS) AF: 0.0143 AC: 21 AN: 1472

South Asian (SAS) AF: 0.0145 AC: 19 AN: 1306

European-Finnish (FIN) AF: 0.0253 AC: 104 AN: 4118

Middle Eastern (MID) AF: 0.0125 AC: 1 AN: 80

European-Non Finnish (NFE) AF: 0.0209 AC: 471 AN: 22488

Other (OTH) AF: 0.0160 AC: 10 AN: 624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.79
DANN	Benign	0.18
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111358030; hg19: chr13-23894754; COSMIC: COSV54556975;