19-7550002-C-G

Variant names:

• chr19-7550002-C-G
• rs62111288
• NM_001166114.2:c.1704C>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001166114.2(PNPLA6):​c.1704C>G​(p.Pro568Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,022 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (16 hom., cov: 33)
  • Exomes 𝑓: 0.013 (139 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -8.15

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-7550002-C-G is Benign according to our data. Variant chr19-7550002-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 240692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00958 (1460/152324) while in subpopulation NFE AF= 0.0147 (1000/68022). AF 95% confidence interval is 0.0139. There are 16 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.1704C>G	p.Pro568Pro	synonymous_variant	Exon 14 of 32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.1704C>G	p.Pro568Pro	synonymous_variant	Exon 14 of 32	1	NM_001166114.2	ENSP00000473211.1

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1460 AN: 152206 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.0103 AC: 2581 AN: 251334 Hom.: 18 AF XY: 0.0101 AC XY: 1368 AN XY: 135896

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00578

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0131 AC: 19123 AN: 1461698 Hom.: 139 Cov.: 34 AF XY: 0.0127 AC XY: 9263 AN XY: 727152

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00630

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00958 AC: 1460 AN: 152324 Hom.: 16 Cov.: 33 AF XY: 0.00893 AC XY: 665 AN XY: 74492

Gnomad4 AFR AF: 0.00305

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00467 Hom.: 1

Bravo AF: 0.00878

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 14, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PNPLA6: BP4, BP7, BS1, BS2 -

Hereditary spastic paraplegia 39 Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary spastic paraplegia Benign:1

Nov 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs62111288; hg19: chr19-7614888; COSMIC: COSV99653594; COSMIC: COSV99653594;