chr4-52028899-G-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Extracellular (size 231) in uniprot entity SGCB_HUMAN there are 44 pathogenic changes around while only 2 benign (96%) 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 chr4-52028899-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.452C>T	p.Thr151Ile	missense_variant	Exon 4 of 6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.242C>T	p.Thr81Ile	missense_variant	Exon 3 of 5		XP_047272030.1
SGCB	XM_047416075.1	c.155C>T	p.Thr52Ile	missense_variant	Exon 3 of 5		XP_047272031.1
SGCB	XM_047416076.1	c.155C>T	p.Thr52Ile	missense_variant	Exon 3 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.452C>T	p.Thr151Ile	missense_variant	Exon 4 of 6	1	NM_000232.5	ENSP00000370839.6

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-52895065;