chr6-56618254-T-C

Variant names:

• chr6-56618254-T-C
• rs12209266
• NM_001723.7:c.5780A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001723.7(DST):​c.5780A>G​(p.His1927Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,614,150 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (51 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 1.54
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032410324).
• BP6: Variant 6-56618254-T-C is Benign according to our data. Variant chr6-56618254-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 381713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00427 (651/152332) while in subpopulation NFE AF = 0.00707 (481/68036). AF 95% confidence interval is 0.00655. There are 2 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001723.7	MANE Plus Clinical	c.5780A>G	p.His1927Arg	missense	Exon 23 of 24	NP_001714.1
	DST	NM_001374736.1	MANE Select	c.4930-3770A>G		intron	N/A	NP_001361665.1
	DST	NM_001374734.1		c.4957-3770A>G		intron	N/A	NP_001361663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.5780A>G	p.His1927Arg	missense	Exon 23 of 24	ENSP00000359801.6
	DST	ENST00000680361.1	MANE Select	c.4930-3770A>G		intron	N/A	ENSP00000505098.1
	DST	ENST00000244364.10	TSL:1	c.3319-3770A>G		intron	N/A	ENSP00000244364.6

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00414 AC: 1041 AN: 251230 AF XY: 0.00411

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00569

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00615 AC: 8987 AN: 1461818 Hom.: 51 Cov.: 36 AF XY: 0.00592 AC XY: 4307 AN XY: 727220

African (AFR) AF: 0.000866 AC: 29 AN: 33472

American (AMR) AF: 0.00157 AC: 70 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86252

European-Finnish (FIN) AF: 0.00623 AC: 333 AN: 53412

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00734 AC: 8161 AN: 1111978

Other (OTH) AF: 0.00498 AC: 301 AN: 60386

GnomAD4 genome AF: 0.00427 AC: 651 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00415 AC XY: 309 AN XY: 74490

African (AFR) AF: 0.00130 AC: 54 AN: 41566

American (AMR) AF: 0.00314 AC: 48 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00599 Hom.: 9

Bravo AF: 0.00376

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00422 AC: 512

EpiCase AF: 0.00665

EpiControl AF: 0.00664

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 14, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25790160)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DST: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary sensory and autonomic neuropathy type 6 Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DST-related disorder Benign:1

Feb 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.2
DANN	Benign	0.95
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.5
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.034
Sift	Benign	0.12	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.089
MVP		0.17
ClinPred		0.0023	T
GERP RS		3.4
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: rs12209266; hg19: chr6-56483052;