11-27657850-A-C

Position:

• chr11-27657850-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001709.5(BDNF):​c.715T>G​(p.Cys239Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BDNF NM_001709.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BDNF	NM_001709.5	c.715T>G	p.Cys239Gly	missense_variant	2/2	ENST00000356660.9	NP_001700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BDNF	ENST00000356660.9	c.715T>G	p.Cys239Gly	missense_variant	2/2	1	NM_001709.5	ENSP00000349084.4
BDNF	ENST00000533131.5	c.715T>G	p.Cys239Gly	missense_variant	2/2	1		ENSP00000432727.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

BDNF-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The BDNF c.961T>G variant is predicted to result in the amino acid substitution p.Cys321Gly. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Benign	0.94
DEOGEN2	Uncertain	0.64	D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;D;.;.;.;.;.;.;D;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;M;.;M;M;M;M;M;M;.;M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;B;D;D;D;D;D;D;P;D;D;D;D;D;D;D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);.;Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);.;Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);.;
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-27679397;