Genetic Variant PDCD10:p.Val192Ile (chr3-167684373-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_007217.4(PDCD10):c.574G>A(p.Val192Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,597,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

PDCD10
NM_007217.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.19

Publications

1 publications found

Variant links:

Genes affected

PDCD10 (HGNC:8761): (programmed cell death 10) This gene encodes an evolutionarily conserved protein associated with cell apoptosis. The protein interacts with the serine/threonine protein kinase MST4 to modulate the extracellular signal-regulated kinase (ERK) pathway. It also interacts with and is phosphoryated by serine/threonine kinase 25, and is thought to function in a signaling pathway essential for vascular developent. Mutations in this gene are one cause of cerebral cavernous malformations, which are vascular malformations that cause seizures and cerebral hemorrhages. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

PDCD10 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PDCD10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04316616).

BP6

Variant 3-167684373-C-T is Benign according to our data. Variant chr3-167684373-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344108.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000475 (72/151608) while in subpopulation NFE AF = 0.000883 (60/67962). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007217.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDCD10	NM_007217.4	MANE Select	c.574G>A	p.Val192Ile	missense	Exon 9 of 9	NP_009148.2
PDCD10	NM_001439202.1		c.574G>A	p.Val192Ile	missense	Exon 9 of 9	NP_001426131.1
PDCD10	NM_001439204.1		c.574G>A	p.Val192Ile	missense	Exon 8 of 8	NP_001426133.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDCD10	ENST00000392750.7	TSL:1 MANE Select	c.574G>A	p.Val192Ile	missense	Exon 9 of 9	ENSP00000376506.2	Q9BUL8
PDCD10	ENST00000473645.6	TSL:1	c.574G>A	p.Val192Ile	missense	Exon 9 of 9	ENSP00000418317.2	Q9BUL8
PDCD10	ENST00000497056.6	TSL:1	c.574G>A	p.Val192Ile	missense	Exon 8 of 8	ENSP00000420553.2	Q9BUL8

Frequencies

GnomAD3 genomes

AF:

0.000475

AC:

AN:

151494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000960

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000883

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.000374

AC:

AN:

251104

AF XY:

0.000368

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000749

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000677

AC:

979

AN:

1446112

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

470

AN XY:

720424

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33108

American (AMR)

AF:

0.000179

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85944

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000852

AC:

936

AN:

1098080

Other (OTH)

AF:

0.000418

AC:

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000475

AC:

AN:

151608

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41308

American (AMR)

AF:

0.00

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0000960

AC:

AN:

10420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000883

AC:

AN:

67962

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral cavernous malformation 3 (3)

Cerebral cavernous malformation (1)

PDCD10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.12

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.67

M_CAP

Benign

0.0047

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

1.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.18

REVEL

Benign

0.048

Sift

Benign

0.84

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.11

MVP

0.17

MPC

0.55

ClinPred

0.011

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.12

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over