ENST00000598334.5:c.2062G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000598334.5(DTNA):c.2062G>A(p.Glu688Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,535,714 control chromosomes in the GnomAD database, including 43,444 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8928 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34516 hom. )

Consequence

DTNA
ENST00000598334.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.98

Publications

19 publications found

Variant links:

Genes affected

DTNA (HGNC:3057): (dystrobrevin alpha) The protein encoded by this gene belongs to the dystrobrevin subfamily of the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC), which consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Mutations in this gene are associated with left ventricular noncompaction with congenital heart defects. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DTNA Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
left ventricular noncompaction 1
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Meniere disease
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DTNA links:

ENSG00000278464 (HGNC:):

ENSG00000278464 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4859438E-4).

BP6

Variant 18-34890327-G-A is Benign according to our data. Variant chr18-34890327-G-A is described in ClinVar as Benign. ClinVar VariationId is 137181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1 link	c.*2593G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6 link	c.*2593G>A		3_prime_UTR_variant	Exon 23 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

45116

AN:

151828

Hom.:

8893

Cov.:

show subpopulations

Gnomad AFR

AF:

0.563

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.204

Gnomad OTH

AF:

0.275

GnomAD2 exomes

AF:

0.202

AC:

27673

AN:

136942

AF XY:

0.202

show subpopulations

Gnomad AFR exome

AF:

0.575

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.212

AC:

293115

AN:

1383768

Hom.:

34516

Cov.:

AF XY:

0.211

AC XY:

144206

AN XY:

682832

show subpopulations

African (AFR)

AF:

0.575

AC:

18165

AN:

31590

American (AMR)

AF:

0.143

AC:

5096

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7042

AN:

25182

East Asian (EAS)

AF:

0.0163

AC:

581

AN:

35734

South Asian (SAS)

AF:

0.218

AC:

17257

AN:

79234

European-Finnish (FIN)

AF:

0.178

AC:

6033

AN:

33886

Middle Eastern (MID)

AF:

0.284

AC:

1617

AN:

5694

European-Non Finnish (NFE)

AF:

0.208

AC:

224085

AN:

1078848

Other (OTH)

AF:

0.229

AC:

13239

AN:

57902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

14530

29060

43591

58121

72651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7958

15916

23874

31832

39790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.298

AC:

45218

AN:

151946

Hom.:

8928

Cov.:

AF XY:

0.292

AC XY:

21708

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.563

AC:

23321

AN:

41406

American (AMR)

AF:

0.197

AC:

3000

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

964

AN:

3466

East Asian (EAS)

AF:

0.0160

AC:

AN:

5182

South Asian (SAS)

AF:

0.205

AC:

984

AN:

4804

European-Finnish (FIN)

AF:

0.190

AC:

2007

AN:

10548

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.204

AC:

13889

AN:

67960

Other (OTH)

AF:

0.275

AC:

581

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1400

2800

4201

5601

7001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.233

Hom.:

21564

Bravo

AF:

0.312

TwinsUK

AF:

0.207

AC:

768

ALSPAC

AF:

0.208

AC:

802

ExAC

AF:

0.213

AC:

3406

Asia WGS

AF:

0.160

AC:

556

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 22, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.93

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.29

MetaRNN

Benign

0.00015

PhyloP100

2.0

Sift4G

Uncertain

0.042

Vest4

0.088

MPC

0.36

GERP RS

4.7

gMVP

0.36

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over