2-178477196-C-A

Variant names:

• chr2-178477196-C-A
• rs533896380
• NM_181342.3:c.239G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181342.3(FKBP7):​c.239G>T​(p.Gly80Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FKBP7 NM_181342.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• Publications: 2 publications found

Genes affected

FKBP7 (HGNC:3723): (FKBP prolyl isomerase 7) The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. Members of this family exhibit PPIase activity and function as molecular chaperones. A similar protein in mouse is located in the endoplasmic reticulum and binds calcium. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181342.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP7	NM_181342.3	MANE Select	c.239G>T	p.Gly80Val	missense	Exon 2 of 4	NP_851939.1	Q9Y680-2
	FKBP7	NM_001135212.2		c.239G>T	p.Gly80Val	missense	Exon 2 of 4	NP_001128684.1	Q9Y680-3
	FKBP7	NM_001410972.1		c.239G>T	p.Gly80Val	missense	Exon 2 of 3	NP_001397901.1	B4DRE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP7	ENST00000424785.7	TSL:1 MANE Select	c.239G>T	p.Gly80Val	missense	Exon 2 of 4	ENSP00000413152.2	Q9Y680-2
	FKBP7	ENST00000434643.6	TSL:1	c.239G>T	p.Gly80Val	missense	Exon 2 of 4	ENSP00000415486.2	Q9Y680-3
	FKBP7	ENST00000233092.10	TSL:1	n.239G>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000233092.6	Q9Y680-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246366 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458050 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725292

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111052

Other (OTH) AF: 0.00 AC: 0 AN: 60276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.93	D
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.42		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.98
MPC		0.45
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.79
Mutation Taster		=26/74	disease causing

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: rs533896380; hg19: chr2-179341923;