chr4-52021671-A-T

Variant names:

• chr4-52021671-A-T
• rs116538326
• NM_000232.5:c.*2286T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000232.5(SGCB):​c.*2286T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 152,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCB NM_000232.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.02
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-52021671-A-T is Benign according to our data. Variant chr4-52021671-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 348857.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00653 (994/152206) while in subpopulation NFE AF = 0.00963 (655/68024). AF 95% confidence interval is 0.00902. There are 3 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.*2286T>A		3_prime_UTR	Exon 6 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.*2286T>A		3_prime_UTR	Exon 5 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.*2286T>A		3_prime_UTR	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.*2286T>A		3_prime_UTR	Exon 6 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.*2286T>A		3_prime_UTR	Exon 6 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.*2286T>A		3_prime_UTR	Exon 5 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 994 AN: 152088 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00963

Gnomad OTH AF: 0.0124

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00653 AC: 994 AN: 152206 Hom.: 3 Cov.: 32 AF XY: 0.00628 AC XY: 467 AN XY: 74422

African (AFR) AF: 0.00352 AC: 146 AN: 41474

American (AMR) AF: 0.00608 AC: 93 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00699 Hom.: 1

Bravo AF: 0.00648

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Qualitative or quantitative defects of beta-sarcoglycan (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.35
PhyloP100		1.0
Mutation Taster		=100/0	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: rs116538326; hg19: chr4-52887837;