chr4-52028807-T-C

Variant names:

• chr4-52028807-T-C
• rs751427686
• NM_000232.5:c.544A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000232.5(SGCB):​c.544A>G​(p.Thr182Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T182P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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 Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2E

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

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000232.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-52028807-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 466604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 4-52028807-T-C is Pathogenic according to our data. Variant chr4-52028807-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2203542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.544A>G	p.Thr182Ala	missense	Exon 4 of 6	NP_000223.1
	SGCB	NM_001440519.1		c.334A>G	p.Thr112Ala	missense	Exon 3 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.247A>G	p.Thr83Ala	missense	Exon 5 of 7	NP_001427449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.544A>G	p.Thr182Ala	missense	Exon 4 of 6	ENSP00000370839.6
	SGCB	ENST00000899666.1		c.532A>G	p.Thr178Ala	missense	Exon 4 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.544A>G	p.Thr182Ala	missense	Exon 4 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Sialidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.024	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.91		Gain of glycosylation at Y184 (P = 0.0138)
MVP		0.99
MPC		0.25
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.31
gMVP		0.79
Mutation Taster		=3/97	disease causing

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: rs751427686; hg19: chr4-52894973;