chr18-34755697-A-G

Variant names:

• chr18-34755697-A-G
• rs6650657
• NM_001386795.1:c.-1-279A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001386795.1(DTNA):​c.-1-279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 388,908 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (8 hom.)
• Consequence: DTNA NM_001386795.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.244
• Publications: 0 publications found

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):

• 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
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DTNA-AS1 (HGNC:58208):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-34755697-A-G is Benign according to our data. Variant chr18-34755697-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 669424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1527/152306) while in subpopulation AFR AF = 0.035 (1454/41560). AF 95% confidence interval is 0.0335. There are 15 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1527 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386795.1. 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
	DTNA	NM_001386795.1	MANE Select	c.-1-279A>G		intron	N/A	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.-1-279A>G		intron	N/A	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001198938.2		c.-1-279A>G		intron	N/A	NP_001185867.1	Q9Y4J8-15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.-1-279A>G		intron	N/A	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.-1-279A>G		intron	N/A	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.-1-279A>G		intron	N/A	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1520 AN: 152188 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00764

GnomAD4 exome AF: 0.00136 AC: 322 AN: 236602 Hom.: 8 AF XY: 0.00114 AC XY: 145 AN XY: 127396

African (AFR) AF: 0.0368 AC: 263 AN: 7144

American (AMR) AF: 0.00196 AC: 21 AN: 10708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6624

East Asian (EAS) AF: 0.00 AC: 0 AN: 12708

South Asian (SAS) AF: 0.000338 AC: 12 AN: 35554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10118

Middle Eastern (MID) AF: 0.00211 AC: 2 AN: 948

European-Non Finnish (NFE) AF: 0.0000357 AC: 5 AN: 139894

Other (OTH) AF: 0.00147 AC: 19 AN: 12904

GnomAD4 genome AF: 0.0100 AC: 1527 AN: 152306 Hom.: 15 Cov.: 33 AF XY: 0.00993 AC XY: 740 AN XY: 74490

African (AFR) AF: 0.0350 AC: 1454 AN: 41560

American (AMR) AF: 0.00320 AC: 49 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0115 Hom.: 19

Bravo AF: 0.0117

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.72
PhyloP100		0.24
PromoterAI		0.0056	Neutral
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: rs6650657; hg19: chr18-32335661;