chr2-218339877-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015488.5(PNKD):​c.331A>C​(p.Thr111Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. T111A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074816346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5	c.331A>C	p.Thr111Pro	missense_variant	Exon 3 of 10	ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.331A>C	p.Thr111Pro	missense_variant	Exon 3 of 10	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 18 AN: 149808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000239

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0507 AC: 8381 AN: 165384 AF XY: 0.0580

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0450

Gnomad EAS exome AF: 0.0308

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0312

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00426 AC: 5956 AN: 1398740 Hom.: 0 Cov.: 31 AF XY: 0.00553 AC XY: 3814 AN XY: 690310

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00266 AC: 85 AN: 31906

American (AMR) AF: 0.0195 AC: 730 AN: 37410

Ashkenazi Jewish (ASJ) AF: 0.00763 AC: 183 AN: 23996

East Asian (EAS) AF: 0.00500 AC: 183 AN: 36612

South Asian (SAS) AF: 0.0111 AC: 862 AN: 77324

European-Finnish (FIN) AF: 0.0172 AC: 790 AN: 45968

Middle Eastern (MID) AF: 0.0192 AC: 90 AN: 4692

European-Non Finnish (NFE) AF: 0.00267 AC: 2896 AN: 1082746

Other (OTH) AF: 0.00236 AC: 137 AN: 58086

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000133 AC: 20 AN: 149910 Hom.: 0 Cov.: 31 AF XY: 0.000192 AC XY: 14 AN XY: 73054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000490 AC: 2 AN: 40854

American (AMR) AF: 0.0000662 AC: 1 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

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: 0.000239 AC: 16 AN: 67042

Other (OTH) AF: 0.00 AC: 0 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000469624), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00539 Hom.: 0

ExAC AF: 0.00357 AC: 431

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.76
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.25
MPC		0.18
ClinPred		0.0090	T
GERP RS		-0.12
Varity_R		0.16
gMVP		0.61
Mutation Taster		=90/10	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; COSMIC: COSV51230896; COSMIC: COSV51230896;