12-48922031-T-C

Position:

• chr12-48922031-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016594.3(FKBP11):​c.559A>G​(p.Lys187Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FKBP11 NM_016594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56

Genes affected

FKBP11 (HGNC:18624): (FKBP prolyl isomerase 11) FKBP11 belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. The peptidyl-prolyl isomerase activity of FKBP proteins is inhibited by the immunosuppressant compounds FK506 and rapamycin (Rulten et al., 2006 [PubMed 16596453]).[supplied by OMIM, Mar 2008]

ENSG00000272822 (HGNC:):

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31113324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP11	NM_016594.3	c.559A>G	p.Lys187Glu	missense_variant	6/6	ENST00000550765.6	NP_057678.1
FKBP11	NM_001143781.2	c.253A>G	p.Lys85Glu	missense_variant	5/5		NP_001137253.1
FKBP11	XM_047428939.1	c.802A>G	p.Lys268Glu	missense_variant	7/7		XP_047284895.1
FKBP11	XM_047428940.1	c.685A>G	p.Lys229Glu	missense_variant	6/6		XP_047284896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP11	ENST00000550765.6	c.559A>G	p.Lys187Glu	missense_variant	6/6	1	NM_016594.3	ENSP00000449751.1
ENSG00000272822	ENST00000398092.4	c.384+17624A>G		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460542 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2024

The c.559A>G (p.K187E) alteration is located in exon 6 (coding exon 6) of the FKBP11 gene. This alteration results from a A to G substitution at nucleotide position 559, causing the lysine (K) at amino acid position 187 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.75	N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.31	T;D
Polyphen		1.0	.;D
Vest4		0.43
MutPred		0.31		.;Loss of loop (P = 0.0031);
MVP		0.87
MPC		0.25
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.65

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: rs1368136887; hg19: chr12-49315814;