11-27658008-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001709.5(BDNF):c.557G>A(p.Cys186Tyr) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BDNF NM_001709.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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)

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-27658008-C-T is Pathogenic according to our data. Variant chr11-27658008-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BDNF	NM_001709.5	c.557G>A	p.Cys186Tyr	missense_variant	2/2	ENST00000356660.9
BDNF-AS	NR_033312.1	n.306-233C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BDNF	ENST00000356660.9	c.557G>A	p.Cys186Tyr	missense_variant	2/2	1	NM_001709.5	P4
BDNF-AS	ENST00000651238.1	n.380-233C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Goettingen

Oct 13, 2020

ACMG criteria used for classification: PS2, PM2, PP3, BP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Benign	0.97
DEOGEN2	Uncertain	0.65	D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;M;M;M;.;M;M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
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;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Vest4		0.96
MutPred		0.90		Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);.;Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);.;Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);Loss of methylation at K185 (P = 0.0306);.;
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		1.0

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

Other links and lift over

dbSNP: rs1852795747; hg19: chr11-27679555;