4-52038263-C-T

Variant names:

• chr4-52038263-C-T
• rs1553940969
• NM_000232.5:c.-4G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000232.5(SGCB):​c.-4G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000874 in 1,144,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: SGCB NM_000232.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.-4G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000381431.10	NP_000223.1
SGCB	NM_001440519.1	c.-4G>A		5_prime_UTR_variant	Exon 1 of 5		NP_001427448.1
SGCB	NM_001440520.1	c.-411G>A		5_prime_UTR_variant	Exon 1 of 7		NP_001427449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.-4G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6
SGCB	ENST00000506357.5	n.-19G>A		upstream_gene_variant		5		ENSP00000421235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.74e-7 AC: 1 AN: 1144228 Hom.: 0 Cov.: 31 AF XY: 0.00000181 AC XY: 1 AN XY: 553252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23842

American (AMR) AF: 0.00 AC: 0 AN: 17222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17240

East Asian (EAS) AF: 0.00 AC: 0 AN: 25566

South Asian (SAS) AF: 0.0000280 AC: 1 AN: 35680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 951866

Other (OTH) AF: 0.00 AC: 0 AN: 45684

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.0010
PromoterAI		0.34	Neutral

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: rs1553940969; hg19: chr4-52904429;