15-72265140-C-G

Variant names:

• chr15-72265140-C-G
• rs377347451
• NM_001323532.2:c.269G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001323532.2(PARP6):​c.269G>C​(p.Arg90Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R90Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PARP6 NM_001323532.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82
• Publications: 2 publications found

Genes affected

PARP6 (HGNC:26921): (poly(ADP-ribose) polymerase family member 6) Enables protein ADP-ribosylase activity. Involved in protein auto-ADP-ribosylation and protein mono-ADP-ribosylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323532.2. 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
	PARP6	NM_001323532.2	MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 7 of 24	NP_001310461.1	Q2NL67-1
	PARP6	NM_001323525.2		c.269G>C	p.Arg90Pro	missense	Exon 7 of 24	NP_001310454.1
	PARP6	NM_001323528.2		c.269G>C	p.Arg90Pro	missense	Exon 7 of 24	NP_001310457.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP6	ENST00000569795.6	TSL:5 MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 7 of 24	ENSP00000456348.1	Q2NL67-1
	PARP6	ENST00000567974.5	TSL:1	c.125G>C	p.Arg42Pro	missense	Exon 3 of 20	ENSP00000455815.1	H3BQK2
	PARP6	ENST00000419739.7	TSL:1	c.269G>C	p.Arg90Pro	missense	Exon 5 of 20	ENSP00000403265.3	F5H3B4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249146 AF XY: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461052 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111348

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.019
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.40
Sift	Benign	0.097	T
Sift4G	Benign	0.35	T
Polyphen		0.015	B
Vest4		0.83
MutPred		0.53		Loss of helix (P = 0.0138)
MVP		0.37
MPC		0.52
ClinPred		0.58	D
GERP RS		5.6
Varity_R		0.56
gMVP		0.84

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: rs377347451; hg19: chr15-72557481;