rs113264142

Variant names:

• chr19-7554964-C-T
• rs113264142
• NM_001166114.2:c.2706C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001166111.2(PNPLA6):​c.2736C>T​(p.Gly912Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,590,092 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: PNPLA6 NM_001166111.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.817
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-7554964-C-T is Benign according to our data. Variant chr19-7554964-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.817 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1630/152310) while in subpopulation AFR AF = 0.0372 (1548/41562). AF 95% confidence interval is 0.0357. There are 25 homozygotes in GnomAd4. There are 757 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166111.2. 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.2706C>T	p.Gly902Gly	synonymous	Exon 22 of 32	NP_001159586.1
	PNPLA6	NM_001166111.2		c.2736C>T	p.Gly912Gly	synonymous	Exon 24 of 34	NP_001159583.1
	PNPLA6	NM_001166113.1		c.2592C>T	p.Gly864Gly	synonymous	Exon 25 of 35	NP_001159585.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.2706C>T	p.Gly902Gly	synonymous	Exon 22 of 32	ENSP00000473211.1
	PNPLA6	ENST00000221249.10	TSL:1	c.2592C>T	p.Gly864Gly	synonymous	Exon 25 of 35	ENSP00000221249.5
	PNPLA6	ENST00000450331.7	TSL:1	c.2592C>T	p.Gly864Gly	synonymous	Exon 25 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 152192 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00297 AC: 643 AN: 216658 AF XY: 0.00208

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000593

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00111 AC: 1593 AN: 1437782 Hom.: 35 Cov.: 36 AF XY: 0.000940 AC XY: 672 AN XY: 714790

African (AFR) AF: 0.0393 AC: 1308 AN: 33288

American (AMR) AF: 0.00210 AC: 91 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39312

South Asian (SAS) AF: 0.0000709 AC: 6 AN: 84640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39174

Middle Eastern (MID) AF: 0.00193 AC: 10 AN: 5186

European-Non Finnish (NFE) AF: 0.0000415 AC: 46 AN: 1107206

Other (OTH) AF: 0.00219 AC: 131 AN: 59764

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152310 Hom.: 25 Cov.: 33 AF XY: 0.0102 AC XY: 757 AN XY: 74476

African (AFR) AF: 0.0372 AC: 1548 AN: 41562

American (AMR) AF: 0.00320 AC: 49 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00373 Hom.: 6

Bravo AF: 0.0126

Asia WGS AF: 0.00289 AC: 10 AN: 3478

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 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	-0.46
CADD	Benign	8.8
DANN	Benign	0.76
PhyloP100		-0.82
PromoterAI		0.028	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs113264142; hg19: chr19-7619850;