rs8192466

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001709.5(BDNF):c.5C>T(p.Thr2Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,614,178 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 7 hom. )

Consequence

BDNF
NM_001709.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

BDNF (HGNC:1033): (brain derived neurotrophic factor) This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders. [provided by RefSeq, Nov 2015]

BDNF links:

BDNF (HGNC:):

BDNF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05125609).

BS2

High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BDNF	NM_001709.5 linkuse as main transcript	c.5C>T	p.Thr2Ile	missense_variant	2/2	ENST00000356660.9	NP_001700.2	P23560-1A0A0E3SU01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BDNF	ENST00000356660.9 linkuse as main transcript	c.5C>T	p.Thr2Ile	missense_variant	2/2	1	NM_001709.5	ENSP00000349084.4		P23560-1
BDNF	ENST00000533131.5 linkuse as main transcript	c.5C>T	p.Thr2Ile	missense_variant	2/2	1		ENSP00000432727.1		P23560-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

202

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00129

AC:

323

AN:

250832

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00230

AC:

3364

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1655

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.000955

Gnomad4 NFE exome

AF:

0.00271

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00132

AC:

201

AN:

152322

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00225

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Congenital central hypoventilation

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

BDNF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.026

MetaRNN

Benign

0.051

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

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

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

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.29

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.20

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

Polyphen

0.99

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

Vest4

0.68

MVP

0.86

MPC

1.6

ClinPred

0.053

GERP RS

6.0

Varity_R

0.34

gMVP

0.86

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