chr2-218344505-G-C

Variant names:

• chr2-218344505-G-C
• rs139825405
• NM_015488.5:c.919G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000273077.9(PNKD):​c.919G>C​(p.Glu307Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,440,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E307K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PNKD ENST00000273077.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35084006).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000273077.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.919G>C	p.Glu307Gln	missense	Exon 9 of 10	NP_056303.3
	PNKD	NM_022572.4		c.847G>C	p.Glu283Gln	missense	Exon 8 of 9	NP_072094.1
	CATIP-AS2	NR_125777.1		n.120+6655C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.919G>C	p.Glu307Gln	missense	Exon 9 of 10	ENSP00000273077.4
	PNKD	ENST00000258362.7	TSL:1	c.847G>C	p.Glu283Gln	missense	Exon 8 of 9	ENSP00000258362.3
	PNKD	ENST00000685415.1		c.1036G>C	p.Glu346Gln	missense	Exon 10 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440304 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714304

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.00 AC: 0 AN: 41136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38808

South Asian (SAS) AF: 0.00 AC: 0 AN: 82992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101390

Other (OTH) AF: 0.00 AC: 0 AN: 59602

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.090	T
Sift4G	Benign	0.53	T
Polyphen		0.96	D
Vest4		0.35
MutPred		0.31		Gain of MoRF binding (P = 0.0451)
MVP		0.77
MPC		0.33
ClinPred		0.72	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.44
Mutation Taster		=81/19	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: rs139825405; hg19: chr2-219209228;