3-33864074-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_013374.6(PDCD6IP):c.2189C>T(p.Ser730Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,612,542 control chromosomes in the GnomAD database, including 29,772 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2954 hom., cov: 33)

Exomes 𝑓: 0.18 ( 26818 hom. )

Consequence

PDCD6IP
NM_013374.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00

Publications

43 publications found

Variant links:

Genes affected

PDCD6IP (HGNC:8766): (programmed cell death 6 interacting protein) This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15. [provided by RefSeq, Jan 2012]

PDCD6IP Gene-Disease associations (from GenCC):

microcephaly 29, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

PDCD6IP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024302304).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013374.6. 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
	PDCD6IP	NM_013374.6	MANE Select	c.2189C>T	p.Ser730Leu	missense	Exon 16 of 18	NP_037506.2
	PDCD6IP	NM_001162429.3		c.2204C>T	p.Ser735Leu	missense	Exon 16 of 18	NP_001155901.1	Q8WUM4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDCD6IP	ENST00000307296.8	TSL:1 MANE Select	c.2189C>T	p.Ser730Leu	missense	Exon 16 of 18	ENSP00000307387.3	Q8WUM4-1
PDCD6IP	ENST00000457054.6	TSL:1	c.2204C>T	p.Ser735Leu	missense	Exon 16 of 18	ENSP00000411825.2	Q8WUM4-2
PDCD6IP	ENST00000965906.1		c.2309C>T	p.Ser770Leu	missense	Exon 17 of 19	ENSP00000635965.1

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27842

AN:

152050

Hom.:

2940

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.392

Gnomad SAS

AF:

0.293

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.228

AC:

57358

AN:

251050

AF XY:

0.222

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.407

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.177

AC:

259103

AN:

1460374

Hom.:

26818

Cov.:

AF XY:

0.180

AC XY:

130833

AN XY:

726494

show subpopulations

African (AFR)

AF:

0.147

AC:

4931

AN:

33448

American (AMR)

AF:

0.413

AC:

18458

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5036

AN:

26118

East Asian (EAS)

AF:

0.387

AC:

15335

AN:

39654

South Asian (SAS)

AF:

0.287

AC:

24729

AN:

86090

European-Finnish (FIN)

AF:

0.131

AC:

7014

AN:

53408

Middle Eastern (MID)

AF:

0.166

AC:

954

AN:

5764

European-Non Finnish (NFE)

AF:

0.154

AC:

171368

AN:

1110912

Other (OTH)

AF:

0.187

AC:

11278

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

9455

18910

28364

37819

47274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6410

12820

19230

25640

32050

<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:

0.183

AC:

27903

AN:

152168

Hom.:

2954

Cov.:

AF XY:

0.188

AC XY:

14002

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.159

AC:

6612

AN:

41490

American (AMR)

AF:

0.298

AC:

4561

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

671

AN:

3472

East Asian (EAS)

AF:

0.393

AC:

2032

AN:

5174

South Asian (SAS)

AF:

0.292

AC:

1409

AN:

4822

European-Finnish (FIN)

AF:

0.133

AC:

1409

AN:

10610

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10676

AN:

68000

Other (OTH)

AF:

0.198

AC:

417

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1152

2304

3456

4608

5760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.174

Hom.:

11590

Bravo

AF:

0.193

TwinsUK

AF:

0.156

AC:

579

ALSPAC

AF:

0.157

AC:

605

ESP6500AA

AF:

0.157

AC:

693

ESP6500EA

AF:

0.153

AC:

1313

ExAC

AF:

0.220

AC:

26721

Asia WGS

AF:

0.325

AC:

1129

AN:

3478

EpiCase

AF:

0.156

EpiControl

AF:

0.151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

Eigen

Benign

0.00027

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

PhyloP100

2.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

REVEL

Benign

0.063

Sift

Uncertain

0.023

Sift4G

Benign

0.10

Polyphen

0.54

Vest4

0.11

MPC

0.11

ClinPred

0.021

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.10

gMVP

0.25

Mutation Taster

=97/3

polymorphism (auto)

(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