rs199941631

Variant names:

• chr5-272771-C-G
• rs199941631
• NM_013232.4:c.162C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-272771-C-G
• chr5-272771-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

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
• Publications: 0 publications found

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]

ENSG00000286001 (HGNC:):

PDCD6-DT (HGNC:55580): (PDCD6 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37967685).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013232.4. 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
	PDCD6	NM_013232.4	MANE Select	c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 6	NP_037364.1	O75340-1
	PDCD6	NM_001267556.2		c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 6	NP_001254485.1	O75340-2
	PDCD6	NM_001267557.2		c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 4	NP_001254486.1	A0A087WZ38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD6	ENST00000264933.9	TSL:1 MANE Select	c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 6	ENSP00000264933.4	O75340-1
	PDCD6	ENST00000507528.5	TSL:1	c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 6	ENSP00000423815.1	O75340-2
	PDCD6	ENST00000509581.5	TSL:1	c.162C>G	p.Asn54Lys	missense splice_region	Exon 2 of 3	ENSP00000422691.1	Q86W51

Frequencies

GnomAD3 genomes AF: 0.0000871 AC: 12 AN: 137794 Hom.: 1 Cov.: 27

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

GnomAD2 exomes AF: 0.000114 AC: 27 AN: 237846 AF XY: 0.000123

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 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.: 4 Cov.: 30 AF XY: 0.000145 AC XY: 104 AN XY: 719644

African (AFR) AF: 0.0000344 AC: 1 AN: 29076

American (AMR) AF: 0.000184 AC: 8 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.000190 AC: 210 AN: 1104860

Other (OTH) AF: 0.0000841 AC: 5 AN: 59434

GnomAD4 genome AF: 0.0000870 AC: 12 AN: 137854 Hom.: 1 Cov.: 27 AF XY: 0.0000890 AC XY: 6 AN XY: 67426

African (AFR) AF: 0.00 AC: 0 AN: 29956

American (AMR) AF: 0.0000695 AC: 1 AN: 14382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000165 AC: 11 AN: 66830

Other (OTH) AF: 0.00 AC: 0 AN: 1948

Alfa AF: 0.000119 Hom.: 0

ExAC AF: 0.0000833 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-1.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.61
MutPred		0.49		Gain of ubiquitination at N54 (P = 0.0121)
MVP		0.98
MPC		3.8
ClinPred		0.49	T
GERP RS		-3.4
PromoterAI		-0.076	Neutral
Varity_R		0.78
gMVP		0.73
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs199941631; hg19: chr5-272886; COSMIC: COSV53776815; COSMIC: COSV53776815;