rs138607224

Variant names:

• chr6-56627276-G-A
• rs138607224
• NM_001374736.1:c.4650C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001374736.1(DST):​c.4650C>T​(p.Ser1550Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,610,902 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.280
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.131).
• BP6: Variant 6-56627276-G-A is Benign according to our data. Variant chr6-56627276-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541488.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.

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.4650C>T	p.Ser1550Ser	synonymous	Exon 34 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.3039C>T	p.Ser1013Ser	synonymous	Exon 20 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.4677C>T	p.Ser1559Ser	synonymous	Exon 34 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.4650C>T	p.Ser1550Ser	synonymous	Exon 34 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.3039C>T	p.Ser1013Ser	synonymous	Exon 20 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.3039C>T	p.Ser1013Ser	synonymous	Exon 20 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151800 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000917 AC: 23 AN: 250812 AF XY: 0.0000811

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000439 AC: 64 AN: 1458984 Hom.: 0 Cov.: 29 AF XY: 0.0000399 AC XY: 29 AN XY: 726062

African (AFR) AF: 0.000269 AC: 9 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110022

Other (OTH) AF: 0.000481 AC: 29 AN: 60316

GnomAD4 genome AF: 0.000276 AC: 42 AN: 151918 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74232

African (AFR) AF: 0.000580 AC: 24 AN: 41414

American (AMR) AF: 0.000787 AC: 12 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000238

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DST-related disorder (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	-0.50
CADD	Benign	6.9
DANN	Benign	0.73
PhyloP100		-0.28
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: rs138607224; hg19: chr6-56492074; COSMIC: COSV55000566;