rs4770403

Variant names:

• chr13-23180988-G-A
• rs4770403
• NM_000231.3:c.-88G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378245.1(SGCG):​c.-152+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,152 control chromosomes in the GnomAD database, including 1,846 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1846 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: SGCG NM_001378245.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.306
• Publications: 17 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]

SGCG Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 13-23180988-G-A is Benign according to our data. Variant chr13-23180988-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 311478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378245.1. 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.-88G>A		5_prime_UTR	Exon 1 of 8	NP_000222.2	Q13326
	SGCG	NM_001378246.1		c.-239G>A		5_prime_UTR	Exon 1 of 9	NP_001365175.1	Q13326
	SGCG	NM_001378244.1		c.54+20342G>A		intron	N/A	NP_001365173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	ENST00000218867.4	TSL:1 MANE Select	c.-88G>A		5_prime_UTR	Exon 1 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.-88G>A		5_prime_UTR	Exon 1 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.-239G>A		5_prime_UTR	Exon 1 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22881 AN: 152030 Hom.: 1838 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.151 AC: 22905 AN: 152148 Hom.: 1846 Cov.: 32 AF XY: 0.147 AC XY: 10907 AN XY: 74368

African (AFR) AF: 0.101 AC: 4174 AN: 41516

American (AMR) AF: 0.125 AC: 1910 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 866 AN: 3464

East Asian (EAS) AF: 0.138 AC: 712 AN: 5178

South Asian (SAS) AF: 0.111 AC: 537 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1394 AN: 10576

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12617 AN: 67988

Other (OTH) AF: 0.156 AC: 328 AN: 2106

Alfa AF: 0.174 Hom.: 8163

Bravo AF: 0.148

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	-0.81
CADD	Benign	2.3
DANN	Benign	0.71
PhyloP100		0.31
PromoterAI		-0.018	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs4770403; hg19: chr13-23755127;