NM_015488.5:c.331A>G

Variant names:

• chr2-218339877-A-G
• rs202190131
• NM_015488.5:c.331A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015488.5(PNKD):​c.331A>G​(p.Thr111Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,548,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T111T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.764
• Publications: 4 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]

CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00935021).
• BP6: Variant 2-218339877-A-G is Benign according to our data. Variant chr2-218339877-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334313.
• BS2: High AC in GnomAd4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015488.5. 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
	PNKD	NM_015488.5	MANE Select	c.331A>G	p.Thr111Ala	missense	Exon 3 of 10	NP_056303.3
	PNKD	NM_022572.4		c.259A>G	p.Thr87Ala	missense	Exon 2 of 9	NP_072094.1	Q8N490-3
	CATIP-AS2	NR_125777.1		n.120+11283T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.331A>G	p.Thr111Ala	missense	Exon 3 of 10	ENSP00000273077.4	Q8N490-1
	PNKD	ENST00000258362.7	TSL:1	c.259A>G	p.Thr87Ala	missense	Exon 2 of 9	ENSP00000258362.3	Q8N490-3
	PNKD	ENST00000685415.1		c.448A>G	p.Thr150Ala	missense	Exon 4 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 18 AN: 149812 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00256

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000447

Gnomad OTH AF: 0.000488

GnomAD2 exomes AF: 0.000266 AC: 44 AN: 165384 AF XY: 0.000282

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000178 AC: 249 AN: 1398830 Hom.: 2 Cov.: 31 AF XY: 0.000183 AC XY: 126 AN XY: 690360

African (AFR) AF: 0.00 AC: 0 AN: 31908

American (AMR) AF: 0.0000267 AC: 1 AN: 37426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23998

East Asian (EAS) AF: 0.00544 AC: 199 AN: 36614

South Asian (SAS) AF: 0.000129 AC: 10 AN: 77328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45992

Middle Eastern (MID) AF: 0.000426 AC: 2 AN: 4692

European-Non Finnish (NFE) AF: 0.0000259 AC: 28 AN: 1082784

Other (OTH) AF: 0.000155 AC: 9 AN: 58088

GnomAD4 genome AF: 0.000120 AC: 18 AN: 149914 Hom.: 0 Cov.: 31 AF XY: 0.000178 AC XY: 13 AN XY: 73054

African (AFR) AF: 0.00 AC: 0 AN: 40854

American (AMR) AF: 0.00 AC: 0 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00257 AC: 13 AN: 5060

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000447 AC: 3 AN: 67044

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

Alfa AF: 0.0000859 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000215 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Paroxysmal nonkinesigenic dyskinesia 1 (2)
-	-	1	not provided (1)
-	-	1	Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.73
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.27
Sift	Benign	0.33	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.22
MVP		0.30
MPC		0.14
ClinPred		0.015	T
GERP RS		-0.12
Varity_R		0.035
gMVP		0.46
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs202190131; hg19: chr2-219204600;