5-311332-G-A

Variant names:

• chr5-311332-G-A
• rs772846590
• NM_013232.4:c.407G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013232.4(PDCD6):​c.407G>A​(p.Arg136Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PDCD6 NM_013232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

PDCD6 (HGNC:8765): (programmed cell death 6) This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is also located on the short arm of chromosome 5. [provided by RefSeq, May 2012]

ENSG00000286001 (HGNC:):

PDCD6-AHRR (HGNC:54724): (PDCD6-AHRR readthrough (NMD candidate)) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2550105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD6	NM_013232.4	c.407G>A	p.Arg136Gln	missense_variant	Exon 5 of 6	ENST00000264933.9	NP_037364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD6	ENST00000264933.9	c.407G>A	p.Arg136Gln	missense_variant	Exon 5 of 6	1	NM_013232.4	ENSP00000264933.4
ENSG00000286001	ENST00000651543.1	n.*1777G>A		non_coding_transcript_exon_variant	Exon 22 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*1777G>A		3_prime_UTR_variant	Exon 22 of 24			ENSP00000499215.1
PDCD6-AHRR	ENST00000675395.1	n.208+7111G>A		intron_variant	Intron 3 of 13			ENSP00000502570.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250980 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461796 Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407G>A (p.R136Q) alteration is located in exon 5 (coding exon 5) of the PDCD6 gene. This alteration results from a G to A substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 to be replaced by a glutamine (Q). 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	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.70	N;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;.;.;N;N
REVEL	Benign	0.24
Sift	Benign	0.24	T;.;.;T;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.12
MutPred		0.45		Loss of MoRF binding (P = 0.0139);.;.;.;.;
MVP		0.87
MPC		0.66
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772846590; hg19: chr5-311447;