Genetic Variant NM_000231.3:c.312T>G (chr13-23250644-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000231.3(SGCG):c.312T>G(p.Leu104Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,602,866 control chromosomes in the GnomAD database, including 134,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L104L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.47 ( 18343 hom., cov: 32)

Exomes 𝑓: 0.39 ( 116268 hom. )

Consequence

SGCG
NM_000231.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.711

Publications

19 publications found

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]

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)

SGCG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 13-23250644-T-G is Benign according to our data. Variant chr13-23250644-T-G is described in ClinVar as Benign. ClinVar VariationId is 92654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.711 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCG	NM_000231.3	MANE Select	c.312T>G	p.Leu104Leu	synonymous	Exon 4 of 8	NP_000222.2	Q13326
SGCG	NM_001378244.1		c.366T>G	p.Leu122Leu	synonymous	Exon 4 of 8	NP_001365173.1
SGCG	NM_001378245.1		c.312T>G	p.Leu104Leu	synonymous	Exon 5 of 9	NP_001365174.1	Q13326

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCG	ENST00000218867.4	TSL:1 MANE Select	c.312T>G	p.Leu104Leu	synonymous	Exon 4 of 8	ENSP00000218867.3	Q13326
SGCG	ENST00000942469.1		c.312T>G	p.Leu104Leu	synonymous	Exon 4 of 9	ENSP00000612528.1
SGCG	ENST00000876364.1		c.312T>G	p.Leu104Leu	synonymous	Exon 5 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

71218

AN:

151864

Hom.:

18319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.678

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.334

Gnomad EAS

AF:

0.686

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.400

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.402

GnomAD2 exomes

AF:

0.419

AC:

105004

AN:

250602

AF XY:

0.409

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.684

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.374

GnomAD4 exome

AF:

0.392

AC:

568812

AN:

1450884

Hom.:

116268

Cov.:

AF XY:

0.390

AC XY:

281664

AN XY:

722524

show subpopulations

African (AFR)

AF:

0.684

AC:

22713

AN:

33196

American (AMR)

AF:

0.379

AC:

16908

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

8736

AN:

26070

East Asian (EAS)

AF:

0.701

AC:

27780

AN:

39650

South Asian (SAS)

AF:

0.376

AC:

32349

AN:

85996

European-Finnish (FIN)

AF:

0.405

AC:

21617

AN:

53374

Middle Eastern (MID)

AF:

0.251

AC:

1445

AN:

5752

European-Non Finnish (NFE)

AF:

0.375

AC:

413033

AN:

1102178

Other (OTH)

AF:

0.404

AC:

24231

AN:

60030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

14476

28952

43427

57903

72379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13140

26280

39420

52560

65700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.469

AC:

71295

AN:

151982

Hom.:

18343

Cov.:

AF XY:

0.465

AC XY:

34553

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.677

AC:

28066

AN:

41444

American (AMR)

AF:

0.379

AC:

5787

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

1157

AN:

3468

East Asian (EAS)

AF:

0.685

AC:

3542

AN:

5168

South Asian (SAS)

AF:

0.375

AC:

1805

AN:

4812

European-Finnish (FIN)

AF:

0.400

AC:

4221

AN:

10554

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.375

AC:

25507

AN:

67958

Other (OTH)

AF:

0.408

AC:

860

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1786

3572

5357

7143

8929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.414

Hom.:

40412

Bravo

AF:

0.482

EpiCase

AF:

0.353

EpiControl

AF:

0.348

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Autosomal recessive limb-girdle muscular dystrophy type 2C (4)

not provided (2)

Limb-girdle muscular dystrophy, recessive (1)

Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.1

(source)

DANN

Benign

0.61

PhyloP100

0.71

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over