rs762579551

Variant names:

• chr18-34848346-G-C
• rs762579551
• NM_001386795.1:c.1397G>C
• DTNA p.Arg466Thr

Your query was ambiguous. Multiple possible variants found:

• chr18-34848346-G-C
• chr18-34848346-G-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001386795.1(DTNA):​c.1397G>C​(p.Arg466Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.06
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• BS2: High AC in GnomAdExome4 at 20 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.1397G>C	p.Arg466Thr	missense	Exon 14 of 23	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.1397G>C	p.Arg466Thr	missense	Exon 14 of 23	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.1316G>C	p.Arg439Thr	missense	Exon 13 of 22	NP_001381.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.1397G>C	p.Arg466Thr	missense	Exon 14 of 23	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.1136G>C	p.Arg379Thr	missense	Exon 12 of 20	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.1136G>C	p.Arg379Thr	missense	Exon 12 of 22	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251286 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727176

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Left ventricular noncompaction 1 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Varity_R		0.84
gMVP		0.77
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762579551;

hg19: chr18-32428310;