Genetic Variant SGCG:p.Arg3Ser (chr13-23203701-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000231.3(SGCG):c.7C>A(p.Arg3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,082 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SGCG
NM_000231.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.36

Publications

1 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 Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, Orphanet

SGCG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.7C>A	p.Arg3Ser	missense	Exon 2 of 8	NP_000222.2	Q13326
SGCG	NM_001378244.1		c.61C>A	p.Arg21Ser	missense	Exon 2 of 8	NP_001365173.1
SGCG	NM_001378245.1		c.7C>A	p.Arg3Ser	missense	Exon 3 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.7C>A	p.Arg3Ser	missense	Exon 2 of 8	ENSP00000218867.3	Q13326
SGCG	ENST00000942469.1		c.7C>A	p.Arg3Ser	missense	Exon 2 of 9	ENSP00000612528.1
SGCG	ENST00000876364.1		c.7C>A	p.Arg3Ser	missense	Exon 3 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

247672

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459082

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725686

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110134

Other (OTH)

AF:

0.00

AC:

AN:

60280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.41

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

PhyloP100

4.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.36

Sift

Uncertain

0.011

Sift4G

Uncertain

0.027

Polyphen

0.38

Vest4

0.70

MutPred

0.25

Gain of glycosylation at R3 (P = 0.008)

MVP

0.77

MPC

0.17

ClinPred

0.91

GERP RS

1.7

Varity_R

0.18

gMVP

0.85

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over