chr6-35665261-G-C

Position:

• chr6-35665261-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_004117.4(FKBP5):​c.-19-22418C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 151,294 control chromosomes in the GnomAD database, including 31,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: 𝑓 0.64 (31356 hom., cov: 28)
• Consequence: FKBP5 NM_004117.4 intron
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: -0.257

Genes affected

FKBP5 (HGNC:3721): (FKBP prolyl isomerase 5) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 6-35665261-G-C is Pathogenic according to our data. Variant chr6-35665261-G-C is described in ClinVar as [Likely_risk_allele]. Clinvar id is 1702944.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.-19-22418C>G		intron_variant		ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.-19-22418C>G		intron_variant			NP_001139247.1
FKBP5	NM_001145776.2	c.-19-22418C>G		intron_variant			NP_001139248.1
FKBP5	NM_001145777.2	c.-19-22418C>G		intron_variant			NP_001139249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.-19-22418C>G		intron_variant		1	NM_004117.4	ENSP00000349811	P1
FKBP5	ENST00000536438.5	c.-19-22418C>G		intron_variant		1		ENSP00000444810	P1
FKBP5	ENST00000539068.5	c.-19-22418C>G		intron_variant		1		ENSP00000441205	P1
FKBP5	ENST00000542713.1	c.-19-22418C>G		intron_variant		2		ENSP00000442340

Frequencies

GnomAD3 genomes AF: 0.641 AC: 96989 AN: 151202 Hom.: 31340 Cov.: 28

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.647

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.641 AC: 97044 AN: 151294 Hom.: 31356 Cov.: 28 AF XY: 0.646 AC XY: 47761 AN XY: 73886

Gnomad4 AFR AF: 0.548

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.678

Gnomad4 SAS AF: 0.663

Gnomad4 FIN AF: 0.763

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.645

Alfa AF: 0.564 Hom.: 1630

Bravo AF: 0.628

Asia WGS AF: 0.656 AC: 2279 AN: 3478

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Susceptibility to severe depressive disorder Pathogenic:1

Likely risk allele, no assertion criteria provided

case-control

Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology

Jul 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.61

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: rs9380525; hg19: chr6-35633038;