chr2-218342136-C-T

Variant names:

• chr2-218342136-C-T
• rs777714592
• NM_015488.5:c.773C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_015488.5(PNKD):​c.773C>T​(p.Ser258Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• 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]

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

MIR6810 (HGNC:49987): (microRNA 6810) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 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.773C>T	p.Ser258Phe	missense	Exon 7 of 10	NP_056303.3
	PNKD	NM_022572.4		c.701C>T	p.Ser234Phe	missense	Exon 6 of 9	NP_072094.1	Q8N490-3
	CATIP-AS2	NR_125777.1		n.120+9024G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.773C>T	p.Ser258Phe	missense	Exon 7 of 10	ENSP00000273077.4	Q8N490-1
	PNKD	ENST00000258362.7	TSL:1	c.701C>T	p.Ser234Phe	missense	Exon 6 of 9	ENSP00000258362.3	Q8N490-3
	PNKD	ENST00000685415.1		c.890C>T	p.Ser297Phe	missense	Exon 8 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250060 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460572 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726590

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.085
Eigen_PC	Benign	0.072
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.50
Sift	Benign	0.049	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.62		Loss of glycosylation at S258 (P = 0.0591)
MVP		0.80
MPC		0.16
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.32
gMVP		0.92
Mutation Taster		=59/41	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: rs777714592; hg19: chr2-219206859; COSMIC: COSV51235640; COSMIC: COSV51235640;