dbSNP rs2382817: PNKD:c.236+14946A>C (chr2-218286495-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_015488.5(PNKD):c.236+14946A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 151,968 control chromosomes in the GnomAD database, including 28,373 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 28353 hom., cov: 31)

Exomes 𝑓: 0.64 ( 20 hom. )

Consequence

PNKD
NM_015488.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.37

Publications

76 publications found

Variant links:

Genes affected

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

PNKD links:

TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMBIM1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5 link	c.236+14946A>C		intron_variant	Intron 2 of 9	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415
TMBIM1	NM_022152.6 link	c.-40-4314T>G		intron_variant	Intron 1 of 11	ENST00000258412.8	NP_071435.2	Q969X1B3KSM0A0A024R472

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 link	c.236+14946A>C		intron_variant	Intron 2 of 9	1	NM_015488.5	ENSP00000273077.4		Q8N490-1
TMBIM1	ENST00000258412.8 link	c.-40-4314T>G		intron_variant	Intron 1 of 11	1	NM_022152.6	ENSP00000258412.3		Q969X1

Frequencies

GnomAD3 genomes

AF:

0.610

AC:

92588

AN:

151742

Hom.:

28318

Cov.:

show subpopulations

Gnomad AFR

AF:

0.635

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.644

Gnomad FIN

AF:

0.714

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.593

Gnomad OTH

AF:

0.575

GnomAD4 exome

AF:

0.639

AC:

AN:

108

Hom.:

Cov.:

AF XY:

0.616

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.634

AC:

AN:

Other (OTH)

AF:

0.700

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.541

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.610

AC:

92672

AN:

151860

Hom.:

28353

Cov.:

AF XY:

0.613

AC XY:

45530

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.635

AC:

26275

AN:

41398

American (AMR)

AF:

0.554

AC:

8452

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2080

AN:

3468

East Asian (EAS)

AF:

0.605

AC:

3106

AN:

5136

South Asian (SAS)

AF:

0.644

AC:

3099

AN:

4814

European-Finnish (FIN)

AF:

0.714

AC:

7519

AN:

10528

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.593

AC:

40285

AN:

67946

Other (OTH)

AF:

0.575

AC:

1206

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1892

3784

5675

7567

9459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.600

Hom.:

56821

Bravo

AF:

0.599

Asia WGS

AF:

0.669

AC:

2331

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.13

(source)

DANN

Benign

0.60

PhyloP100

-1.4

PromoterAI

0.0022

Neutral

(source)

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over