NM_014871.6:c.535A>C

Variant names:

• chr12-56328276-T-G
• rs1918496
• NM_014871.6:c.535A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014871.6(PAN2):​c.535A>C​(p.Ile179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,607,762 control chromosomes in the GnomAD database, including 768,342 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.85 (58916 hom., cov: 32)
  • Exomes 𝑓: 0.98 (709426 hom.)
• Consequence: PAN2 NM_014871.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59
• Publications: 31 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.695101E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

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>C	p.Ile179Leu	missense	Exon 4 of 26	NP_055686.4
	PAN2	NM_001127460.4		c.535A>C	p.Ile179Leu	missense	Exon 4 of 26	NP_001120932.2	Q504Q3-1
	PAN2	NM_001394699.1		c.535A>C	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>C	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000388231.3	Q504Q3-2
	PAN2	ENST00000425394.7	TSL:1	c.535A>C	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000401721.2	Q504Q3-1
	PAN2	ENST00000257931.9	TSL:1	c.535A>C	p.Ile179Leu	missense	Exon 4 of 26	ENSP00000257931.5	Q504Q3-3

Frequencies

GnomAD3 genomes AF: 0.850 AC: 129276 AN: 152076 Hom.: 58908 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.903

GnomAD2 exomes AF: 0.959 AC: 236720 AN: 246810 AF XY: 0.970

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.984 AC: 1432197 AN: 1455568 Hom.: 709426 Cov.: 47 AF XY: 0.986 AC XY: 713556 AN XY: 723592

African (AFR) AF: 0.468 AC: 15607 AN: 33346

American (AMR) AF: 0.968 AC: 42583 AN: 43994

Ashkenazi Jewish (ASJ) AF: 0.981 AC: 25182 AN: 25660

East Asian (EAS) AF: 1.00 AC: 39629 AN: 39630

South Asian (SAS) AF: 0.999 AC: 85302 AN: 85382

European-Finnish (FIN) AF: 1.00 AC: 53143 AN: 53146

Middle Eastern (MID) AF: 0.973 AC: 5589 AN: 5744

European-Non Finnish (NFE) AF: 0.999 AC: 1107212 AN: 1108574

Other (OTH) AF: 0.964 AC: 57950 AN: 60092

GnomAD4 genome AF: 0.850 AC: 129319 AN: 152194 Hom.: 58916 Cov.: 32 AF XY: 0.855 AC XY: 63655 AN XY: 74422

African (AFR) AF: 0.482 AC: 19991 AN: 41438

American (AMR) AF: 0.936 AC: 14320 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3397 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 0.999 AC: 4821 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67871 AN: 68034

Other (OTH) AF: 0.904 AC: 1913 AN: 2116

Alfa AF: 0.941 Hom.: 147898

Bravo AF: 0.829

TwinsUK AF: 0.999 AC: 3703

ALSPAC AF: 0.999 AC: 3851

ESP6500AA AF: 0.494 AC: 2178

ESP6500EA AF: 0.996 AC: 8567

ExAC AF: 0.951 AC: 115375

Asia WGS AF: 0.971 AC: 3377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0020
DANN	Benign	0.69
DEOGEN2	Benign	0.041	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	6.7e-7	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
Polyphen		0.0010	B
Vest4		0.076
MutPred		0.48		Gain of catalytic residue at L174 (P = 0)
MPC		0.51
ClinPred		0.011	T
GERP RS		-8.8
Varity_R		0.044
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs1918496; hg19: chr12-56722060; COSMIC: COSV57755130; COSMIC: COSV57755130;