rs761103593

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM2PM5PP2BP4_Strong

The NM_001166114.2(PNPLA6):c.1680C>G(p.Asp560Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. D560Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PNPLA6
NM_001166114.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.60

Publications

0 publications found

Variant links:

Genes affected

PNPLA6 (HGNC:16268): (patatin like phospholipase domain containing 6) This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

PNPLA6 Gene-Disease associations (from GenCC):

ataxia-hypogonadism-choroidal dystrophy syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
PNPLA6-related spastic paraplegia with or without ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 39
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
cerebellar ataxia-hypogonadism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Laurence-Moon syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
trichomegaly-retina pigmentary degeneration-dwarfism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PNPLA6 links:

ENSG00000307753 (HGNC:):

ENSG00000307753 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-7549976-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2861272.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the PNPLA6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.3547 (above the threshold of 3.09). Trascript score misZ: 3.5139 (above the threshold of 3.09). GenCC associations: The gene is linked to retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, cerebellar ataxia-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, ataxia-hypogonadism-choroidal dystrophy syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, hereditary spastic paraplegia 39, Laurence-Moon syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.05356577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166114.2 link	c.1680C>G	p.Asp560Glu	missense_variant	Exon 14 of 32	ENST00000600737.6	NP_001159586.1	Q8IY17A0A384DVU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6 link	c.1680C>G	p.Asp560Glu	missense_variant	Exon 14 of 32	1	NM_001166114.2	ENSP00000473211.1		A0A384DVU0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251236

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.026

(source)

DANN

Benign

0.75

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.77

.;T;T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.054

T;T;T;T;T

MetaSVM

Benign

-0.56

PhyloP100

-2.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.66

N;N;N;N;.

REVEL

Benign

0.24

Sift

Benign

0.61

T;T;T;T;.

Sift4G

Benign

0.73

T;T;T;T;T

Polyphen

0.0020

B;.;.;B;.

Vest4

0.22

MutPred

0.44

.;.;.;.;Loss of ubiquitination at K557 (P = 0.1287);

MVP

0.32

MPC

0.87

ClinPred

0.023

GERP RS

-10

Varity_R

0.051

gMVP

0.47

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over