18-34794119-C-G

Variant names:

• chr18-34794119-C-G
• rs147759402
• NM_001386795.1:c.231C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386795.1(DTNA):​c.231C>G​(p.Asn77Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. N77D) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.304
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10053378).

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.231C>G	p.Asn77Lys	missense	Exon 4 of 23	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.231C>G	p.Asn77Lys	missense	Exon 4 of 23	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.231C>G	p.Asn77Lys	missense	Exon 3 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.231C>G	p.Asn77Lys	missense	Exon 4 of 23	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.231C>G	p.Asn77Lys	missense	Exon 5 of 20	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.231C>G	p.Asn77Lys	missense	Exon 5 of 22	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251302 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.78
DANN	Benign	0.91
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.30
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.098
Sift	Benign	0.22	T
Sift4G	Benign	0.15	T
Polyphen		0.27	B
Vest4		0.54
MutPred		0.40		Gain of ubiquitination at N77 (P = 0.0203)
MVP		0.61
MPC		0.52
ClinPred		0.073	T
GERP RS		-9.3
Varity_R		0.15
gMVP		0.51
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs147759402; hg19: chr18-32374083; COSMIC: COSV51992738;