15-65263194-C-T

Variant names:

• chr15-65263194-C-T
• rs1246213924
• NM_001316943.2:c.646G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001316943.2(PARP16):​c.646G>A​(p.Glu216Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PARP16 NM_001316943.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

PARP16 (HGNC:26040): (poly(ADP-ribose) polymerase family member 16) Enables kinase binding activity; pentosyltransferase activity; and protein serine/threonine kinase activator activity. Involved in several processes, including IRE1-mediated unfolded protein response; positive regulation of protein serine/threonine kinase activity; and protein ADP-ribosylation. Located in endoplasmic reticulum tubular network and nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP16	NM_001316943.2	c.646G>A	p.Glu216Lys	missense_variant	Exon 4 of 6	ENST00000649807.2	NP_001303872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARP16	ENST00000649807.2	c.646G>A	p.Glu216Lys	missense_variant	Exon 4 of 6		NM_001316943.2	ENSP00000496935.1
PARP16	ENST00000261888.10	c.646G>A	p.Glu216Lys	missense_variant	Exon 4 of 6	1		ENSP00000261888.6
PARP16	ENST00000444347.2	c.301G>A	p.Glu101Lys	missense_variant	Exon 2 of 4	2		ENSP00000396118.2
PARP16	ENST00000560149.5	n.379G>A		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646G>A (p.E216K) alteration is located in exon 4 (coding exon 4) of the PARP16 gene. This alteration results from a G to A substitution at nucleotide position 646, causing the glutamic acid (E) at amino acid position 216 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	.;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.3	M;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.82		Gain of methylation at E216 (P = 3e-04);.;Gain of methylation at E216 (P = 3e-04);
MVP		0.66
MPC		0.68
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs1246213924; hg19: chr15-65555532;