18-34875229-G-T

Variant names:

• chr18-34875229-G-T
• rs192561043
• NM_001386795.1:c.1744-10G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001386795.1(DTNA):​c.1744-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,302 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: DTNA NM_001386795.1 intron
• Scores: Splicing: ADA: 0.9654
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.69
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 18-34875229-G-T is Benign according to our data. Variant chr18-34875229-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 324 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.1744-10G>T		intron	N/A	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.1744-10G>T		intron	N/A	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.1663-10G>T		intron	N/A	NP_001381.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.1744-10G>T		intron	N/A	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.1483-10G>T		intron	N/A	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.1504-10G>T		intron	N/A	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00191 AC: 479 AN: 251042 AF XY: 0.00192

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00225 AC: 3289 AN: 1461048 Hom.: 5 Cov.: 31 AF XY: 0.00219 AC XY: 1595 AN XY: 726718

African (AFR) AF: 0.000478 AC: 16 AN: 33466

American (AMR) AF: 0.00163 AC: 73 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00674 AC: 176 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00403 AC: 215 AN: 53406

Middle Eastern (MID) AF: 0.000886 AC: 5 AN: 5646

European-Non Finnish (NFE) AF: 0.00241 AC: 2673 AN: 1111428

Other (OTH) AF: 0.00214 AC: 129 AN: 60346

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74436

African (AFR) AF: 0.000650 AC: 27 AN: 41548

American (AMR) AF: 0.00196 AC: 30 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00387 AC: 41 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00220

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Left ventricular noncompaction 1 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	DTNA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.82
PhyloP100		1.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.68

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

Other links and lift over

dbSNP: rs192561043; hg19: chr18-32455193;