Variant chr2-25455406-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021907.5(DTNB):c.1168C>T(p.Arg390Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000584 in 1,594,364 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 2 hom. )

Consequence

DTNB
NM_021907.5 missense, splice_region

Scores

Splicing: ADA: 0.9948

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.83

Variant links:

Genes affected

DTNB (HGNC:3058): (dystrobrevin beta) This gene encodes dystrobrevin beta, a component of the dystrophin-associated protein complex (DPC). The DPC consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and dystrobrevin alpha and beta. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Dystrobrevin beta is thought to interact with syntrophin and the DP71 short form of dystrophin. [provided by RefSeq, Mar 2016]

DTNB links:

DTNB (HGNC:):

DTNB links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNB	NM_021907.5 linkuse as main transcript	c.1168C>T	p.Arg390Cys	missense_variant, splice_region_variant	11/21	ENST00000406818.8	NP_068707.1	O60941-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNB	ENST00000406818.8 linkuse as main transcript	c.1168C>T	p.Arg390Cys	missense_variant, splice_region_variant	11/21	1	NM_021907.5	ENSP00000384084.3		O60941-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000531

AC:

117

AN:

220172

Hom.:

AF XY:

0.000539

AC XY:

AN XY:

118764

show subpopulations

Gnomad AFR exome

AF:

0.000231

Gnomad AMR exome

AF:

0.000258

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000562

Gnomad FIN exome

AF:

0.00122

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000605

AC:

872

AN:

1442212

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

444

AN XY:

715634

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000192

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000516

Gnomad4 SAS exome

AF:

0.000616

Gnomad4 FIN exome

AF:

0.000869

Gnomad4 NFE exome

AF:

0.000669

Gnomad4 OTH exome

AF:

0.000402

GnomAD4 genome

AF:

0.000388

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000578

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000242

AC:

ESP6500EA

AF:

0.000475

AC:

ExAC

AF:

0.000538

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.1168C>T (p.R390C) alteration is located in exon 11 (coding exon 10) of the DTNB gene. This alteration results from a C to T substitution at nucleotide position 1168, causing the arginine (R) at amino acid position 390 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.;.;T

Eigen

Benign

0.0095

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.0078

MetaRNN

Benign

0.075

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;L;L;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.45

N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.066

T;D;D;D;D

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.0020, 0.0, 0.51

.;B;B;.;P

Vest4

0.79

MVP

0.44

MPC

0.27

ClinPred

0.042

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -1

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