5-272771-C-G

Position:

chr5-272771-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_013232.4(PDCD6):c.162C>G(p.Asn54Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,584,110 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000087 ( 1 hom., cov: 27)

Exomes 𝑓: 0.00015 ( 4 hom. )

Consequence

PDCD6
NM_013232.4 missense, splice_region

Scores

Splicing: ADA: 0.00003196

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.51

Variant links:

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 links:

PDCD6-AHRR (HGNC:):

PDCD6-AHRR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37967685).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDCD6	NM_013232.4 linkuse as main transcript	c.162C>G	p.Asn54Lys	missense_variant, splice_region_variant	2/6	ENST00000264933.9
PDCD6-AHRR	NR_165159.2 linkuse as main transcript	n.237C>G		splice_region_variant, non_coding_transcript_exon_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDCD6	ENST00000264933.9 linkuse as main transcript	c.162C>G	p.Asn54Lys	missense_variant, splice_region_variant	2/6	1	NM_013232.4	P1	O75340-1

Frequencies

GnomAD3 genomes

AF:

0.0000871

AC:

AN:

137794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000696

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000165

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

237846

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

130030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

224

AN:

1446256

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

104

AN XY:

719644

show subpopulations

Gnomad4 AFR exome

AF:

0.0000344

Gnomad4 AMR exome

AF:

0.000184

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:

0.000190

Gnomad4 OTH exome

AF:

0.0000841

GnomAD4 genome

AF:

0.0000870

AC:

AN:

137854

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

67426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000695

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000165

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

ExAC

AF:

0.0000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.162C>G (p.N54K) 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 162, causing the asparagine (N) at amino acid position 54 to be replaced by a lysine (K). 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

1.0

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T;.;T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.11

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

T;T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.5

M;.;M;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.3

D;.;D;D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0010

D;.;D;D;D;D

Sift4G

Uncertain

0.0020

D;T;D;D;D;D

Polyphen

0.91

P;.;.;.;.;.

Vest4

0.61

MutPred

0.49

Gain of ubiquitination at N54 (P = 0.0121);Gain of ubiquitination at N54 (P = 0.0121);Gain of ubiquitination at N54 (P = 0.0121);Gain of ubiquitination at N54 (P = 0.0121);Gain of ubiquitination at N54 (P = 0.0121);.;

MVP

0.98

MPC

3.8

ClinPred

0.49

GERP RS

-3.4

Varity_R

0.78

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.086

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over