6-56639725-T-G

Variant names:

• chr6-56639725-T-G
• rs777218403
• NM_001374736.1:c.2668A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001374736.1(DST):​c.2668A>C​(p.Arg890Arg) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R890R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.97
• Publications: 0 publications found

Genes affected

DST (HGNC:1090): (dystonin) This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

DST Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-56639725-T-G is Benign according to our data. Variant chr6-56639725-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2922737.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001374736.1	MANE Select	c.2668A>C	p.Arg890Arg	synonymous	Exon 20 of 104	NP_001361665.1
	DST	NM_001723.7	MANE Plus Clinical	c.1057A>C	p.Arg353Arg	synonymous	Exon 6 of 24	NP_001714.1
	DST	NM_001374734.1		c.2695A>C	p.Arg899Arg	synonymous	Exon 20 of 103	NP_001361663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.2668A>C	p.Arg890Arg	synonymous	Exon 20 of 104	ENSP00000505098.1
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.1057A>C	p.Arg353Arg	synonymous	Exon 6 of 24	ENSP00000359801.6
	DST	ENST00000244364.10	TSL:1	c.1057A>C	p.Arg353Arg	synonymous	Exon 6 of 84	ENSP00000244364.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Benign:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777218403; hg19: chr6-56504523;