2-25433991-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021907.5(DTNB):​c.1262G>A​(p.Arg421His) variant causes a missense change. The variant allele was found at a frequency of 0.0000863 in 1,611,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

DTNB
NM_021907.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06146124).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DTNBNM_021907.5 linkc.1262G>A p.Arg421His missense_variant 13/21 ENST00000406818.8 NP_068707.1 O60941-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DTNBENST00000406818.8 linkc.1262G>A p.Arg421His missense_variant 13/211 NM_021907.5 ENSP00000384084.3 O60941-1

Frequencies

GnomAD3 genomes
AF:
0.000187
AC:
28
AN:
149956
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000543
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
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:
0.0000590
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000844
AC:
21
AN:
248888
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135022
show subpopulations
Gnomad AFR exome
AF:
0.000711
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000709
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000760
AC:
111
AN:
1461164
Hom.:
0
Cov.:
30
AF XY:
0.0000660
AC XY:
48
AN XY:
726880
show subpopulations
Gnomad4 AFR exome
AF:
0.000628
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000720
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.000187
AC:
28
AN:
150012
Hom.:
0
Cov.:
31
AF XY:
0.000192
AC XY:
14
AN XY:
73068
show subpopulations
Gnomad4 AFR
AF:
0.000542
Gnomad4 AMR
AF:
0.000132
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000590
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000417
Hom.:
0
Bravo
AF:
0.000272
ESP6500AA
AF:
0.000806
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000116
AC:
14
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsJul 09, 2021The c.1262G>A (p.R421H) alteration is located in exon 13 (coding exon 12) of the DTNB gene. This alteration results from a G to A substitution at nucleotide position 1262, causing the arginine (R) at amino acid position 421 to be replaced by a histidine (H). 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
0.080
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
.;D;.;.;.;.;T;T
Eigen
Benign
0.10
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.061
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
1.8
.;L;L;L;.;.;.;.
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-2.6
D;D;N;D;N;N;N;N
REVEL
Benign
0.091
Sift
Uncertain
0.011
D;D;D;D;D;D;D;D
Sift4G
Benign
0.16
T;T;T;T;T;T;T;T
Polyphen
0.99, 0.011, 0.010, 0.39, 0.89
.;D;B;.;B;.;B;P
Vest4
0.18
MVP
0.47
MPC
0.46
ClinPred
0.16
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.096
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs141947082; hg19: chr2-25656860; COSMIC: COSV104386753; API