NM_015488.5:c.349_351delAATinsTCC

Variant names:

• chr2-218339895-AAT-TCC
• NM_015488.5:c.349_351delAATinsTCC
• PNKD p.Asn117Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_015488.5(PNKD):c.349_351delAATinsTCC (p.Asn117Ser) variant causes a missense, splice region change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N117S: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 468629)

• Frequency: Genomes: not found (cov: 31)
• Consequence: PNKD NM_015488.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• paroxysmal nonkinesigenic dyskinesia 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• paroxysmal nonkinesigenic dyskinesia 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• Tourette syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CATIP-AS2 (HGNC:41079): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_015488.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKD NM_015488.5	MANE Select	c.349_351delAATinsTCC p.Asn117Ser	missensesplice_region	N/A	Prot: NP_056303.3
	PNKD NM_022572.4		c.277_279delAATinsTCC p.Asn93Ser	missensesplice_region	N/A	Prot: NP_072094.1 UniProt:
	CATIP-AS2 NR_125777.1		n.120+11263_120+11265delATTinsGGA	intron	Intron 2 of 3	Prot:

PNKD NM_015488.5

MANE Select

HGVSc / HGVSpc.349_351delAATinsTCCp.Asn117Ser

Exon rankN/A

missensesplice_region

Prot: NP_056303.3

PNKD NM_022572.4

HGVSc / HGVSpc.277_279delAATinsTCCp.Asn93Ser

Exon rankN/A

missensesplice_region

Prot: NP_072094.1UniProt: Q8N490-3

CATIP-AS2 NR_125777.1

HGVSc / HGVSpn.120+11263_120+11265delATTinsGGA

Exon rankIntron 2 of 3

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKD ENST00000273077.9	TSL:1MANE Select	c.349_351delAATinsTCC p.Asn117Ser	missensesplice_region	N/A	Prot: ENSP00000273077.4 UniProt:
	PNKD ENST00000258362.7	TSL:1	c.277_279delAATinsTCC p.Asn93Ser	missensesplice_region	N/A	Prot: ENSP00000258362.3 UniProt:
	PNKD ENST00000685415.1		c.466_468delAATinsTCC p.Asn156Ser	missensesplice_region	N/A	Prot: ENSP00000510415.1 UniProt:

PNKD ENST00000273077.9

TSL:1MANE Select

HGVSc / HGVSpc.349_351delAATinsTCCp.Asn117Ser

Exon rankN/A

missensesplice_region

Prot: ENSP00000273077.4UniProt: Q8N490-1

PNKD ENST00000258362.7

TSL:1

HGVSc / HGVSpc.277_279delAATinsTCCp.Asn93Ser

Exon rankN/A

missensesplice_region

Prot: ENSP00000258362.3UniProt: Q8N490-3

PNKD ENST00000685415.1

HGVSc / HGVSpc.466_468delAATinsTCCp.Asn156Ser

Exon rankN/A

missensesplice_region

Prot: ENSP00000510415.1UniProt: A0A8I5KXK0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr2-219204618;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar