11-27658369-C-T

Variant names:

• chr11-27658369-C-T
• rs6265
• NM_001709.5:c.196G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001143810.2(BDNF):​c.442G>A​(p.Val148Met) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V148L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (2519 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28821 hom.)
• Consequence: BDNF NM_001143810.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 4.94
• Publications: 4138 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143810.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDNF	NM_001709.5	MANE Select	c.196G>A	p.Val66Met	missense	Exon 2 of 2	NP_001700.2
	BDNF	NM_001143810.2		c.442G>A	p.Val148Met	missense	Exon 3 of 3	NP_001137282.1
	BDNF	NM_001143809.2		c.283G>A	p.Val95Met	missense	Exon 2 of 2	NP_001137281.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDNF	ENST00000356660.9	TSL:1 MANE Select	c.196G>A	p.Val66Met	missense	Exon 2 of 2	ENSP00000349084.4
	BDNF	ENST00000438929.5	TSL:1	c.442G>A	p.Val148Met	missense	Exon 3 of 3	ENSP00000414303.1
	BDNF	ENST00000395986.6	TSL:1	c.241G>A	p.Val81Met	missense	Exon 2 of 2	ENSP00000379309.2

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

GnomAD2 exomes AF: 0.195 AC: 48968 AN: 251276 AF XY: 0.199

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 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

African (AFR) AF: 0.0300 AC: 1006 AN: 33480

American (AMR) AF: 0.148 AC: 6609 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5700 AN: 26136

East Asian (EAS) AF: 0.443 AC: 17601 AN: 39700

South Asian (SAS) AF: 0.192 AC: 16604 AN: 86258

European-Finnish (FIN) AF: 0.153 AC: 8189 AN: 53418

Middle Eastern (MID) AF: 0.151 AC: 869 AN: 5768

European-Non Finnish (NFE) AF: 0.188 AC: 209458 AN: 1112006

Other (OTH) AF: 0.188 AC: 11325 AN: 60396

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

African (AFR) AF: 0.0372 AC: 1544 AN: 41542

American (AMR) AF: 0.159 AC: 2434 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3470

East Asian (EAS) AF: 0.473 AC: 2442 AN: 5160

South Asian (SAS) AF: 0.201 AC: 973 AN: 4832

European-Finnish (FIN) AF: 0.151 AC: 1596 AN: 10582

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.187 AC: 12717 AN: 67990

Other (OTH) AF: 0.170 AC: 359 AN: 2108

Alfa AF: 0.183 Hom.: 14165

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	-	Memory impairment, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.074
MPC		1.6
ClinPred		0.026	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.66
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

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