chr4-52028899-G-A

Variant names:

• chr4-52028899-G-A
• rs28936383
• NM_000232.5:c.452C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000232.5(SGCB):​c.452C>T​(p.Thr151Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,426 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. T151R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-52028899-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8712.Status of the report is reviewed_by_expert_panel, 3 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, 0.884

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.452C>T	p.Thr151Ile	missense	Exon 4 of 6	NP_000223.1
	SGCB	NM_001440519.1		c.242C>T	p.Thr81Ile	missense	Exon 3 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.155C>T	p.Thr52Ile	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.452C>T	p.Thr151Ile	missense	Exon 4 of 6	ENSP00000370839.6
	SGCB	ENST00000506357.5	TSL:5	n.*234C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000421235.1
	SGCB	ENST00000514133.1	TSL:5	n.*247C>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000425818.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111672

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.78
Sift	Benign	0.034	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.55		Loss of disorder (P = 0.0432)
MVP		1.0
MPC		0.28
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.62
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936383; hg19: chr4-52895065;