Genetic Variant SGCA:p.Arg221Leu (chr17-50169169-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000023.4(SGCA):c.662G>T(p.Arg221Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R221H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.10

Publications

0 publications found

Variant links:

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA 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 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

SGCA links:

ENSG00000253730 (HGNC:):

ENSG00000253730 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000023.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-50169169-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 497670.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4 link	c.662G>T	p.Arg221Leu	missense_variant	Exon 6 of 10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NR_135553.2 link	n.698G>T		non_coding_transcript_exon_variant	Exon 6 of 9
SGCA	NM_001135697.3 link	c.584+597G>T		intron_variant	Intron 5 of 7		NP_001129169.1	Q16586-2A0A0S2Z4P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 link	c.662G>T	p.Arg221Leu	missense_variant	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PhyloP100

4.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.026

Polyphen

0.97

Vest4

0.39

MutPred

0.85

Loss of disorder (P = 0.0312);

MVP

0.99

MPC

0.99

ClinPred

0.96

GERP RS

5.1

Varity_R

0.24

gMVP

0.75

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.35

Position offset: 11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over