Genetic Variant PDCD10:p.Ala212Thr (chr3-167684313-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007217.4(PDCD10):c.634G>A(p.Ala212Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A212S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDCD10
NM_007217.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.41

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2718385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD10	NM_007217.4 link	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 9	ENST00000392750.7	NP_009148.2	Q9BUL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7 link	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 9	1	NM_007217.4	ENSP00000376506.2		Q9BUL8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1428976

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32848

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39428

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082354

Other (OTH)

AF:

0.00

AC:

AN:

59190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

T;T;T;T;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

.;.;.;D;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.0

N;N;N;.;N;N

PhyloP100

7.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.35

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.016

D;D;D;T;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.87

P;P;P;.;P;P

Vest4

0.37

MutPred

0.31

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.32

MPC

0.67

ClinPred

0.89

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.74

Mutation Taster

=40/60

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over