rs116214830

Variant names:

• chr4-52024120-G-A
• rs116214830
• NM_000232.5:c.794C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_000232.5(SGCB):​c.794C>T​(p.Thr265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T265T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 9.77
• Publications: 1 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, 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015626311).
• BP6: Variant 4-52024120-G-A is Benign according to our data. Variant chr4-52024120-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282121.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000513 (75/1461826) while in subpopulation AFR AF = 0.00128 (43/33478). AF 95% confidence interval is 0.00098. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.794C>T	p.Thr265Ile	missense	Exon 6 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.584C>T	p.Thr195Ile	missense	Exon 5 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.497C>T	p.Thr166Ile	missense	Exon 7 of 7	NP_001427449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.794C>T	p.Thr265Ile	missense	Exon 6 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.782C>T	p.Thr261Ile	missense	Exon 6 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.662C>T	p.Thr221Ile	missense	Exon 5 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251454 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00111

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: 0.000163

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727218

African (AFR) AF: 0.00128 AC: 43 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000872 AC: 5 AN: 5734

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1111996

Other (OTH) AF: 0.000298 AC: 18 AN: 60386

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74480

African (AFR) AF: 0.000987 AC: 41 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (4)
-	1	1	not provided (2)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.042
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.31
Sift	Benign	0.073	T
Sift4G	Benign	0.28	T
Polyphen		0.049	B
Vest4		0.18
MVP		0.97
MPC		0.078
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.060
gMVP		0.40
Mutation Taster		=73/27	polymorphism

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: rs116214830; hg19: chr4-52890286;