2-218339896-A-G

Variant names:

• chr2-218339896-A-G
• rs199572198
• NM_015488.5:c.350A>G
• PNKD p.Asn117Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-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). BP4BP6

The NR_125777.1(CATIP-AS2):n.120+11264T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: NR_125777.1 is not a MANE Select or MANE Plus Clinical transcript for CATIP-AS2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.000261 (AC=418) in the gnomAD database across 1,604,394 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.00443. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: CATIP-AS2 NR_125777.1 intron
• Scores: Splicing: ADA: 0.03235
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.69
• 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NR_125777.1. 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.350A>G p.Asn117Ser	missensesplice_region	Exon 3 of 10	Prot: NP_056303.3
	PNKD NM_022572.4		c.278A>G p.Asn93Ser	missensesplice_region	Exon 2 of 9	Prot: NP_072094.1 UniProt:
	CATIP-AS2 NR_125777.1		n.120+11264T>C	intron	Intron 2 of 3	Prot:

PNKD NM_015488.5

MANE Select

HGVSc / HGVSpc.350A>Gp.Asn117Ser

Exon rankExon 3 of 10

missensesplice_region

Prot: NP_056303.3

PNKD NM_022572.4

HGVSc / HGVSpc.278A>Gp.Asn93Ser

Exon rankExon 2 of 9

missensesplice_region

Prot: NP_072094.1UniProt: Q8N490-3

CATIP-AS2 NR_125777.1

HGVSc / HGVSpn.120+11264T>C

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.350A>G p.Asn117Ser	missensesplice_region	Exon 3 of 10	Prot: ENSP00000273077.4 UniProt:
	PNKD ENST00000258362.7	TSL:1	c.278A>G p.Asn93Ser	missensesplice_region	Exon 2 of 9	Prot: ENSP00000258362.3 UniProt:
	PNKD ENST00000685415.1		c.467A>G p.Asn156Ser	missensesplice_region	Exon 4 of 11	Prot: ENSP00000510415.1 UniProt:

PNKD ENST00000273077.9

TSL:1MANE Select

HGVSc / HGVSpc.350A>Gp.Asn117Ser

Exon rankExon 3 of 10

missensesplice_region

Prot: ENSP00000273077.4UniProt: Q8N490-1

PNKD ENST00000258362.7

TSL:1

HGVSc / HGVSpc.278A>Gp.Asn93Ser

Exon rankExon 2 of 9

missensesplice_region

Prot: ENSP00000258362.3UniProt: Q8N490-3

PNKD ENST00000685415.1

HGVSc / HGVSpc.467A>Gp.Asn156Ser

Exon rankExon 4 of 11

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000138	AC:21	Hom:0	AN:151994	Cov:31
GnomAD2 exomes	AF: 0.000882	AC:214	Hom:	AN:242704	Cov:
GnomAD4 exome	AF: 0.000273	AC:397	Hom:1	AN:1452282	Cov:30
GnomAD4 genome	AF: 0.000138	AC:21	Hom:0	AN:152112	Cov:31
TOPMed (Bravo)	AF: 0.000412	AC:109	Hom:2	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000218	AC:14	Hom:0	AN:64202	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	11012	0.000115 *	2	17422
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.000359	24	66888
SCHEMA(Schizophrenia)	0.000398	43	108076	0.000324	59	181840

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Paroxysmal nonkinesigenic dyskinesia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.84	D
FuncVEP CTI	Benign	0.00052
GPN-Star LLR	N/A	-5.5
GPN-Star score	N/A	5.5
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.036	T
Mutation Taster	N/A	100/0	polymorphism
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	1.7
popEVE	Benign	-2.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.26
Sift	Benign	0.20	T
Sift4G	Benign	0.60	T
Varity_R	N/A	0.044
VESM-3B	Benign	-4.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.032
dbscSNV1_RF	Benign	0.21
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

dbSNP: rs199572198;

hg19: chr2-219204619;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar