12-56319667-T-C

Position:

• chr12-56319667-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_014871.6(PAN2):​c.3044A>G​(p.Asn1015Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: PAN2 NM_014871.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.17

Genes affected

PAN2 (HGNC:20074): (poly(A) specific ribonuclease subunit PAN2) This gene encodes a deadenylase that functions as the catalytic subunit of the polyadenylate binding protein dependent poly(A) nuclease complex. The encoded protein is a magnesium dependent 3' to 5' exoribonuclease that is involved in the degradation of cytoplasmic mRNAs. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

PAN2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAN2. . Gene score misZ 3.1762 (greater than the threshold 3.09). Trascript score misZ 4.8346 (greater than threshold 3.09). GenCC has associacion of gene with multiple congenital anomalies/dysmorphic syndrome-intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03558141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAN2	NM_014871.6	c.3044A>G	p.Asn1015Ser	missense_variant	22/26	ENST00000440411.8	NP_055686.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAN2	ENST00000440411.8	c.3044A>G	p.Asn1015Ser	missense_variant	22/26	1	NM_014871.6	ENSP00000388231.3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 250946 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135650

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000931 AC: 136 AN: 1461516 Hom.: 0 Cov.: 33 AF XY: 0.0000922 AC XY: 67 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74330

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000684 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.3056A>G (p.N1019S) alteration is located in exon 22 (coding exon 21) of the PAN2 gene. This alteration results from a A to G substitution at nucleotide position 3056, causing the asparagine (N) at amino acid position 1019 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.031	T;T;.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;D;D;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.;.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.78	N;.;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.86	T;.;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T
Polyphen		0.022	B;B;B;B;B
Vest4		0.32
MVP		0.37
MPC		0.44
ClinPred		0.018	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs367895499; hg19: chr12-56713451;