rs143924906

Variant names:

• chr6-56629395-C-T
• rs143924906
• NM_001374736.1:c.4330G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001374736.1(DST):​c.4330G>A​(p.Glu1444Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.57
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009847522).
• BP6: Variant 6-56629395-C-T is Benign according to our data. Variant chr6-56629395-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541476.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000335 (51/152274) while in subpopulation EAS AF = 0.00847 (44/5192). AF 95% confidence interval is 0.00649. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001374736.1	MANE Select	c.4330G>A	p.Glu1444Lys	missense	Exon 32 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.2719G>A	p.Glu907Lys	missense	Exon 18 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.4357G>A	p.Glu1453Lys	missense	Exon 32 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.4330G>A	p.Glu1444Lys	missense	Exon 32 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.2719G>A	p.Glu907Lys	missense	Exon 18 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.2719G>A	p.Glu907Lys	missense	Exon 18 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000661 AC: 166 AN: 251270 AF XY: 0.000611

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00854

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461344 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00424 AC: 168 AN: 39602

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111720

Other (OTH) AF: 0.000215 AC: 13 AN: 60368

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00847 AC: 44 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000314

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.00060	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.67
MVP		0.82
MPC		0.60
ClinPred		0.14	T
GERP RS		3.9
gMVP		0.57
Mutation Taster		=63/37	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: rs143924906; hg19: chr6-56494193; COSMIC: COSV99757711;