rs522776

Variant names:

• chr19-7554636-G-A
• rs522776
• NM_001166114.2:c.2547G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7554636-G-A
• chr19-7554636-G-C
• chr19-7554636-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001166114.2(PNPLA6):​c.2547G>A​(p.Ser849Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,614,008 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (94 hom., cov: 32)
  • Exomes 𝑓: 0.028 (682 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.52
• Publications: 8 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-7554636-G-A is Benign according to our data. Variant chr19-7554636-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	NM_001166114.2	MANE Select	c.2547G>A	p.Ser849Ser	synonymous	Exon 21 of 32	NP_001159586.1
	PNPLA6	NM_001166111.2		c.2577G>A	p.Ser859Ser	synonymous	Exon 23 of 34	NP_001159583.1
	PNPLA6	NM_001166113.1		c.2433G>A	p.Ser811Ser	synonymous	Exon 24 of 35	NP_001159585.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.2547G>A	p.Ser849Ser	synonymous	Exon 21 of 32	ENSP00000473211.1
	PNPLA6	ENST00000221249.10	TSL:1	c.2433G>A	p.Ser811Ser	synonymous	Exon 24 of 35	ENSP00000221249.5
	PNPLA6	ENST00000450331.7	TSL:1	c.2433G>A	p.Ser811Ser	synonymous	Exon 24 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4857 AN: 152104 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0269 AC: 6746 AN: 250870 AF XY: 0.0265

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0725

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0278 AC: 40658 AN: 1461786 Hom.: 682 Cov.: 35 AF XY: 0.0277 AC XY: 20125 AN XY: 727212

African (AFR) AF: 0.0373 AC: 1248 AN: 33480

American (AMR) AF: 0.0263 AC: 1174 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 1832 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0112 AC: 967 AN: 86258

European-Finnish (FIN) AF: 0.0225 AC: 1199 AN: 53332

Middle Eastern (MID) AF: 0.0869 AC: 501 AN: 5768

European-Non Finnish (NFE) AF: 0.0285 AC: 31731 AN: 1111996

Other (OTH) AF: 0.0332 AC: 2004 AN: 60396

GnomAD4 genome AF: 0.0319 AC: 4863 AN: 152222 Hom.: 94 Cov.: 32 AF XY: 0.0314 AC XY: 2339 AN XY: 74408

African (AFR) AF: 0.0365 AC: 1515 AN: 41526

American (AMR) AF: 0.0407 AC: 623 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 252 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4820

European-Finnish (FIN) AF: 0.0249 AC: 264 AN: 10618

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0290 AC: 1975 AN: 68004

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0312 Hom.: 64

Bravo AF: 0.0340

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0313

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.54
PhyloP100		-1.5
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: rs522776; hg19: chr19-7619522; COSMIC: COSV55385973; COSMIC: COSV55385973;