Genetic Variant BDNF:p.Arg245Ser (chr11-27657830-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001709.5(BDNF):c.735G>C(p.Arg245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R245R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BDNF
NM_001709.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

0 publications found

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

BDNF-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27645972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDNF	NM_001709.5 link	c.735G>C	p.Arg245Ser	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
BDNF	ENST00000356660.9 link	c.735G>C	p.Arg245Ser	missense_variant	Exon 2 of 2	1	NM_001709.5	ENSP00000349084.4		P23560-1
BDNF	ENST00000533131.5 link	c.735G>C	p.Arg245Ser	missense_variant	Exon 2 of 2	1		ENSP00000432727.1		P23560-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111572

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.0012

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

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

M_CAP

Benign

0.048

MetaRNN

Benign

0.28

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

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.69

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

PhyloP100

1.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.92

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

REVEL

Uncertain

0.33

Sift

Uncertain

0.013

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

Sift4G

Benign

0.79

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

Polyphen

0.13

B;B;B;B;B;B;B;B;B;P;B;B;B;B;B;B;B

Vest4

0.57

MutPred

0.43

Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);.;Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);.;Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);.;

MVP

0.80

MPC

1.1

ClinPred

0.55

GERP RS

5.2

Varity_R

0.30

gMVP

0.57

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over