chr5-272763-C-G

Position:

• chr5-272763-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001267558.2(PDCD6):​c.-57C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,448,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000041 (2 hom.)
• Consequence: PDCD6 NM_001267558.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470

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]

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

PDCD6 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37240136).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD6	NM_013232.4	c.154C>G	p.Leu52Val	missense_variant	2/6	ENST00000264933.9	NP_037364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD6	ENST00000264933.9	c.154C>G	p.Leu52Val	missense_variant	2/6	1	NM_013232.4	ENSP00000264933.4
ENSG00000286001	ENST00000651543.1	n.*1524C>G		non_coding_transcript_exon_variant	19/24			ENSP00000499215.1
PDCD6-AHRR	ENST00000675395.1	n.154C>G		non_coding_transcript_exon_variant	2/14			ENSP00000502570.1
ENSG00000286001	ENST00000651543.1	n.*1524C>G		3_prime_UTR_variant	19/24			ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1448102 Hom.: 2 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 720266

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: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

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

Jun 07, 2023

The c.154C>G (p.L52V) alteration is located in exon 2 (coding exon 2) of the PDCD6 gene. This alteration results from a C to G substitution at nucleotide position 154, causing the leucine (L) at amino acid position 52 to be replaced by a valine (V). 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	0.96
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;T;.;T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.082	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.9	H;.;H;.;H;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;.;D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.51	P;.;.;.;.;.
Vest4		0.68
MutPred		0.71		Loss of stability (P = 0.1126);Loss of stability (P = 0.1126);Loss of stability (P = 0.1126);Loss of stability (P = 0.1126);Loss of stability (P = 0.1126);.;
MVP		0.88
MPC		3.3
ClinPred		0.67	D
GERP RS		0.11
Varity_R		0.41
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-272878; COSMIC: COSV53776009; COSMIC: COSV53776009;