rs6265

chr11-27658369-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001709.5(BDNF):c.196G>A(p.Val66Met) variant causes a missense change. The variant allele was found at a frequency of 0.186 in 1,614,068 control chromosomes in the GnomAD database, including 31,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2519 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28821 hom.)
• Consequence: BDNF NM_001709.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 4.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017960966).
• BP6: Variant 11-27658369-C-T is Benign according to our data. Variant chr11-27658369-C-T is described in ClinVar as [Benign]. Clinvar id is 17697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BDNF	NM_001709.5	c.196G>A	p.Val66Met	missense_variant	2/2	ENST00000356660.9
BDNF-AS	NR_033312.1	n.434C>T		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BDNF	ENST00000356660.9	c.196G>A	p.Val66Met	missense_variant	2/2	1	NM_001709.5	P4
BDNF-AS	ENST00000651238.1	n.508C>T		non_coding_transcript_exon_variant	5/8

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23190 AN: 152064 Hom.: 2519 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.195 AC: 48968 AN: 251276 Hom.: 6030 AF XY: 0.199 AC XY: 26958 AN XY: 135806

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.492

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.190 AC: 277361 AN: 1461886 Hom.: 28821 Cov.: 36 AF XY: 0.191 AC XY: 138787 AN XY: 727244

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.153

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.152 AC: 23187 AN: 152182 Hom.: 2519 Cov.: 32 AF XY: 0.154 AC XY: 11438 AN XY: 74416

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.170

Alfa AF: 0.189 Hom.: 7433

Bravo AF: 0.151

TwinsUK AF: 0.193 AC: 715

ALSPAC AF: 0.180 AC: 693

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.191 AC: 1640

ExAC AF: 0.194 AC: 23513

Asia WGS AF: 0.278 AC: 967 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 18, 2013	Benign with respect to pulmonary disease based on high population frequency, Th is variant has been proposed to be associated with a rnage of psychiatric manife stations though the data is not solid and more recent meta-analyses argue agains t a risk effect. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Memory impairment, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M;M;M;.;M;M;M;M;M;M;.
MutationTaster	Benign	9.8e-7	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;P;D;D;D;D;D;D;D
Vest4		0.074
MPC		1.6
ClinPred		0.026	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.66

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: rs6265; hg19: chr11-27679916; COSMIC: COSV59234714; COSMIC: COSV59234714;