chr4-52024120-G-A

Position:

• chr4-52024120-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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

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_benign. Variant got -5 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
• 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 id is 282121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome 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 gnomad4_exome. There are 39 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.794C>T	p.Thr265Ile	missense_variant	6/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.584C>T	p.Thr195Ile	missense_variant	5/5		XP_047272030.1
SGCB	XM_047416075.1	c.497C>T	p.Thr166Ile	missense_variant	5/5		XP_047272031.1
SGCB	XM_047416076.1	c.497C>T	p.Thr166Ile	missense_variant	5/5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.794C>T	p.Thr265Ile	missense_variant	6/6	1	NM_000232.5	ENSP00000370839.6

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

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251454 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135894

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000298

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

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000207 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 265 of the SGCB protein (p.Thr265Ile). This variant is present in population databases (rs116214830, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 282121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	The SGCB c.794C>T, p.Thr265Ile variant (rs116214830), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 282121). This variant is found in the African population with an allele frequency of 0.1% (28/24,964 alleles) in the Genome Aggregation Database. The threonine at codon 265 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.31). Due to limited information, the clinical significance of the p.Thr265Ile variant is uncertain at this time. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 02, 2023	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

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Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs116214830; hg19: chr4-52890286;