rs1555568966

Variant names:

• chr17-50169091-GGGTATACATTAA-G
• rs1555568966
• NM_000023.4:c.588_599delATACATTAAGGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_000023.4(SGCA):​c.588_599delATACATTAAGGT​(p.Tyr197_Val200del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V196V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SGCA NM_000023.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• Publications: 0 publications found

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA 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 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

ENSG00000253730 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000023.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000023.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4	c.588_599delATACATTAAGGT	p.Tyr197_Val200del	disruptive_inframe_deletion	Exon 6 of 10	ENST00000262018.8	NP_000014.1
SGCA	NR_135553.2	n.624_635delATACATTAAGGT		non_coding_transcript_exon_variant	Exon 6 of 9
SGCA	NM_001135697.3	c.584+523_584+534delATACATTAAGGT		intron_variant	Intron 5 of 7		NP_001129169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.588_599delATACATTAAGGT	p.Tyr197_Val200del	disruptive_inframe_deletion	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:1

Oct 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel in-frame deletion with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SGCA-related disease. This sequence change deletes 12 nucleotides from exon 6 of the SGCA mRNA (c.588_599delATACATTAAGGT). This leads to the deletion of 4 amino acid residues in the SGCA protein (p.Tyr197_Val200del) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555568966; hg19: chr17-48246452;