rs62111288

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-7550002-C-G
• chr19-7550002-C-T
• chr19-7550002-C-A

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. P568P) has been classified 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
• Publications: 6 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000307753 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166114.2. 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
	PNPLA6	NM_001166114.2	MANE Select	c.1704C>G	p.Pro568Pro	synonymous	Exon 14 of 32	NP_001159586.1	A0A384DVU0
	PNPLA6	NM_001166111.2		c.1731C>G	p.Pro577Pro	synonymous	Exon 16 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.1587C>G	p.Pro529Pro	synonymous	Exon 17 of 35	NP_001159585.1	Q8IY17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.1704C>G	p.Pro568Pro	synonymous	Exon 14 of 32	ENSP00000473211.1	A0A384DVU0
	PNPLA6	ENST00000221249.10	TSL:1	c.1587C>G	p.Pro529Pro	synonymous	Exon 17 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.1587C>G	p.Pro529Pro	synonymous	Exon 17 of 35	ENSP00000394348.2	Q8IY17-2

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

GnomAD2 exomes AF: 0.0103 AC: 2581 AN: 251334 AF XY: 0.0101

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 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

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.0135 AC: 604 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 109 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00630 AC: 543 AN: 86258

European-Finnish (FIN) AF: 0.0125 AC: 665 AN: 53232

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0147 AC: 16397 AN: 1112008

Other (OTH) AF: 0.0116 AC: 703 AN: 60392

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

African (AFR) AF: 0.00305 AC: 127 AN: 41586

American (AMR) AF: 0.00896 AC: 137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1000 AN: 68022

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 39 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.76
PhyloP100		-8.1
Mutation Taster		=96/4	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

Other links and lift over

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