4-52038229-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BS1_Supporting

The NM_000232.5(SGCB):c.31C>G(p.Gln11Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,282,918 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q11R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

SGCB
NM_000232.5 missense, splice_region

Scores

Splicing: ADA: 0.006266

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 1.18

Publications

5 publications found

Variant links:

Genes affected

SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

SGCB Gene-Disease associations (from GenCC):

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

SGCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000232.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.0049736 (below the threshold of 3.09). Trascript score misZ: -0.4279 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000451 (51/1131718) while in subpopulation SAS AF = 0.00142 (49/34570). AF 95% confidence interval is 0.0011. There are 1 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCB	NM_000232.5	MANE Select	c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 6	NP_000223.1	Q5U0N0
SGCB	NM_001440519.1		c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 5	NP_001427448.1
SGCB	NM_001440520.1		c.-377C>G		splice_region	Exon 1 of 7	NP_001427449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCB	ENST00000381431.10	TSL:1 MANE Select	c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 6	ENSP00000370839.6	Q16585-1
SGCB	ENST00000899666.1		c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 6	ENSP00000569725.1
SGCB	ENST00000912466.1		c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000233

AC:

AN:

38616

AF XY:

0.000313

show subpopulations

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:

0.0000451

AC:

AN:

1131718

Hom.:

Cov.:

AF XY:

0.0000659

AC XY:

AN XY:

546398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23506

American (AMR)

AF:

0.00

AC:

AN:

16664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16722

East Asian (EAS)

AF:

0.00

AC:

AN:

24618

South Asian (SAS)

AF:

0.00142

AC:

AN:

34570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3054

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

944084

Other (OTH)

AF:

0.0000445

AC:

AN:

44950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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

AF:

0.0000331

AC:

AN:

151200

Hom.:

Cov.:

AF XY:

0.0000677

AC XY:

AN XY:

73890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67634

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000335

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2E (6)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.29

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.1

PhyloP100

1.2

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.11

REVEL

Uncertain

0.52

Sift

Benign

0.21

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.66

MutPred

0.42

Loss of MoRF binding (P = 0.0467)

MVP

0.86

MPC

0.068

ClinPred

0.041

GERP RS

3.0

PromoterAI

0.049

Neutral

(source)

Varity_R

0.12

gMVP

0.23

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0063

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.040

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