rs138185589

chr6-56619262-T-Cchr6-56619262-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001723.7(DST):c.4772A>G(p.Gln1591Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1591P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1214993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.4772A>G	p.Gln1591Arg	missense_variant	23/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-4778A>G		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.4772A>G	p.Gln1591Arg	missense_variant	23/24	1	NM_001723.7
DST	ENST00000680361.1	c.4930-4778A>G		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250172 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460854 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	16
Dann	Benign	0.94
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.058
Sift	Uncertain	0.013	D
Sift4G	Benign	0.64	T
Polyphen		0.18	B
Vest4		0.12
MutPred		0.12		Gain of MoRF binding (P = 0.0153);
MVP		0.30
ClinPred		0.079	T
GERP RS		4.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138185589; hg19: chr6-56484060;