18-34794204-C-G

Position:

chr18-34794204-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001386795.1(DTNA):c.316C>G(p.Gln106Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

DTNA
NM_001386795.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20172662).

BS2

High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNA	NM_001386795.1 linkuse as main transcript	c.316C>G	p.Gln106Glu	missense_variant	4/23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6 linkuse as main transcript	c.316C>G	p.Gln106Glu	missense_variant	4/23	5	NM_001386795.1	ENSP00000405819	P3	Q9Y4J8-17

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251328

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000260

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000236

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000237

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2023	The c.316C>G (p.Q106E) alteration is located in exon 4 (coding exon 3) of the DTNA gene. This alteration results from a C to G substitution at nucleotide position 316, causing the glutamine (Q) at amino acid position 106 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 10, 2014	The Gln106Glu variant in DTNA has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs140768365). Computational prediction tools do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the Gln106Glu variant is uncertain. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 18, 2020

We observed the c.316C>G (p.Q106E) genetic variant in a 57-y.o. male proband diagnosed with left ventricular non-compaction and dilated cardiomyopathy. The p.Q106E genetic variant is present in gnomAD database, its frequency is 2.051e-4. Online in silico tools predict genetic variant p.Q106E to be probably pathogenic. No functional studies are available to date; family DNA samples were likewise unavailable for segregation analysis, therefore, we could only classify the p.Q106E genetic variant as a variant of uncertain clinical significance. -

Left ventricular noncompaction 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 106 of the DTNA protein (p.Gln106Glu). This variant is present in population databases (rs140768365, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 178033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DTNA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

.;.;.;.;T;.;.;.;.;.;.;.;.;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;.;D;D;D;.

M_CAP

Benign

0.034

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.3

L;L;L;.;.;L;L;L;L;L;L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

N;.;N;.;.;.;N;N;.;.;.;N;.;N;N

REVEL

Benign

0.26

Sift

Benign

0.40

T;.;T;.;.;.;T;T;.;.;.;T;.;T;T

Sift4G

Benign

0.64

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.15

B;.;D;.;.;.;.;.;.;P;B;D;.;D;D

Vest4

0.74

MVP

0.83

MPC

0.51

ClinPred

0.15

GERP RS

5.4

Varity_R

0.61

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over