12-56328276-T-A

Variant names:

• chr12-56328276-T-A
• NM_014871.6:c.535A>T
• PAN2 p.Ile179Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014871.6(PAN2):​c.535A>T​(p.Ile179Leu) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAN2 NM_014871.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome-intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07339609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014871.6. 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
	PAN2	NM_014871.6	MANE Select	c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	NP_055686.4
	PAN2	NM_001127460.4		c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	NP_001120932.2	Q504Q3-1
	PAN2	NM_001394699.1		c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	NP_001381628.1	Q504Q3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAN2	ENST00000440411.8	TSL:1 MANE Select	c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000388231.3	Q504Q3-2
	PAN2	ENST00000425394.7	TSL:1	c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000401721.2	Q504Q3-1
	PAN2	ENST00000257931.9	TSL:1	c.535A>T	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000257931.5	Q504Q3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0020
DANN	Benign	0.68
DEOGEN2	Benign	0.041	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		-2.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.086
Sift	Benign	0.28	T
Sift4G	Benign	0.19	T
Varity_R		0.044
gMVP		0.16
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-56722060;