rs115542549

Variant names:

• chr6-56616834-T-C
• rs115542549
• NM_001723.7:c.6633A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001723.7(DST):​c.6633A>G​(p.Ala2211Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,614,152 control chromosomes in the GnomAD database, including 1,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (76 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1418 hom.)
• Consequence: DST NM_001723.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.712
• Publications: 7 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 6-56616834-T-C is Benign according to our data. Variant chr6-56616834-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.712 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3787/152326) while in subpopulation NFE AF = 0.0417 (2834/68026). AF 95% confidence interval is 0.0404. There are 76 homozygotes in GnomAd4. There are 1679 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. 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
	DST	NM_001723.7	MANE Plus Clinical	c.6633A>G	p.Ala2211Ala	synonymous	Exon 24 of 24	NP_001714.1
	DST	NM_001374736.1	MANE Select	c.4930-2350A>G		intron	N/A	NP_001361665.1
	DST	NM_001374734.1		c.4957-2350A>G		intron	N/A	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.6633A>G	p.Ala2211Ala	synonymous	Exon 24 of 24	ENSP00000359801.6
	DST	ENST00000680361.1	MANE Select	c.4930-2350A>G		intron	N/A	ENSP00000505098.1
	DST	ENST00000244364.10	TSL:1	c.3319-2350A>G		intron	N/A	ENSP00000244364.6

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3785 AN: 152208 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0468

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0251 AC: 6297 AN: 251198 AF XY: 0.0258

Gnomad AFR exome AF: 0.00759

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0398 AC: 58168 AN: 1461826 Hom.: 1418 Cov.: 34 AF XY: 0.0391 AC XY: 28435 AN XY: 727212

African (AFR) AF: 0.00636 AC: 213 AN: 33476

American (AMR) AF: 0.0136 AC: 607 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1160 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0218 AC: 1884 AN: 86256

European-Finnish (FIN) AF: 0.0133 AC: 710 AN: 53404

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0462 AC: 51369 AN: 1111986

Other (OTH) AF: 0.0363 AC: 2191 AN: 60392

GnomAD4 genome AF: 0.0249 AC: 3787 AN: 152326 Hom.: 76 Cov.: 32 AF XY: 0.0225 AC XY: 1679 AN XY: 74492

African (AFR) AF: 0.00796 AC: 331 AN: 41586

American (AMR) AF: 0.0139 AC: 213 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 162 AN: 3464

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4830

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2834 AN: 68026

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0342 Hom.: 51

Bravo AF: 0.0244

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0362

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary sensory and autonomic neuropathy type 6 (1)
-	-	1	Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.66
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs115542549; hg19: chr6-56481632;