12-56328276-T-C

Position:

• chr12-56328276-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.535A>G​(p.Ile179Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. I179L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAN2 NM_014871.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59

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]

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=0.067320645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAN2	NM_014871.6	c.535A>G	p.Ile179Val	missense_variant	4/26	ENST00000440411.8	NP_055686.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAN2	ENST00000440411.8	c.535A>G	p.Ile179Val	missense_variant	4/26	1	NM_014871.6	ENSP00000388231	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455588 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 723600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.047
DANN	Benign	0.47
DEOGEN2	Benign	0.037	T;T;.;.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.27	.;T;T;T;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.067	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L;L;L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.48	N;.;N;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.14	T;.;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;.
Polyphen		0.0010	B;B;B;B;B;.
Vest4		0.033
MutPred		0.48		Gain of catalytic residue at L174 (P = 1e-04);Gain of catalytic residue at L174 (P = 1e-04);Gain of catalytic residue at L174 (P = 1e-04);Gain of catalytic residue at L174 (P = 1e-04);Gain of catalytic residue at L174 (P = 1e-04);.;
MVP		0.51
MPC		0.43
ClinPred		0.092	T
GERP RS		-8.8
Varity_R		0.017
gMVP		0.068

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1918496; hg19: chr12-56722060;