11-27658342-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001709.5(BDNF):​c.223C>G​(p.Gln75Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q75H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

BDNF
NM_001709.5 missense

Scores

5
14

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 6.73
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-AS (HGNC:20608): (BDNF antisense RNA)

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=0.1312744).
BP6
Variant 11-27658342-G-C is Benign according to our data. Variant chr11-27658342-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2411940.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BDNFNM_001709.5 linkc.223C>G p.Gln75Glu missense_variant Exon 2 of 2 ENST00000356660.9 NP_001700.2 P23560-1A0A0E3SU01

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BDNFENST00000356660.9 linkc.223C>G p.Gln75Glu missense_variant Exon 2 of 2 1 NM_001709.5 ENSP00000349084.4 P23560-1
BDNFENST00000533131.5 linkc.223C>G p.Gln75Glu missense_variant Exon 2 of 2 1 ENSP00000432727.1 P23560-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251214
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000229
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000218
AC:
318
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.000209
AC XY:
152
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000274
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.000125
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

BDNF-related disorder Uncertain:1
Jul 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BDNF c.469C>G variant is predicted to result in the amino acid substitution p.Gln157Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Benign:1
Jun 17, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.38
T;T;.;T;T;T;T;T;T;.;T;T;T;T;T;T;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
.;.;D;.;.;.;.;.;.;D;D;.;.;.;.;.;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.13
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.2
L;L;.;L;L;L;L;L;L;.;L;L;L;L;L;L;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.56
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.16
Sift
Uncertain
0.024
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.63
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.71
P;P;P;P;P;P;P;P;P;B;P;P;P;P;P;P;P
Vest4
0.15
MVP
0.55
MPC
1.4
ClinPred
0.13
T
GERP RS
6.2
Varity_R
0.093
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs139352447; hg19: chr11-27679889; COSMIC: COSV99043214; COSMIC: COSV99043214; API