chr19-7535969-G-C

Variant names:

• chr19-7535969-G-C
• rs112732576
• NM_001166114.2:c.181G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001166111.2(PNPLA6):​c.208G>C​(p.Val70Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,582,828 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. V70V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: PNPLA6 NM_001166111.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0250
• Publications: 3 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

ENSG00000268614 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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: 3.4354 (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=0.0018042326).
• BP6: Variant 19-7535969-G-C is Benign according to our data. Variant chr19-7535969-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1846/152290) while in subpopulation AFR AF = 0.0428 (1779/41552). AF 95% confidence interval is 0.0412. There are 41 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.181G>C	p.Val61Leu	missense	Exon 1 of 32	NP_001159586.1
	PNPLA6	NM_001166111.2		c.208G>C	p.Val70Leu	missense	Exon 3 of 34	NP_001159583.1
	PNPLA6	NM_001166113.1		c.64G>C	p.Val22Leu	missense	Exon 4 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.181G>C	p.Val61Leu	missense	Exon 1 of 32	ENSP00000473211.1
	PNPLA6	ENST00000221249.10	TSL:1	c.64G>C	p.Val22Leu	missense	Exon 4 of 35	ENSP00000221249.5
	PNPLA6	ENST00000450331.7	TSL:1	c.64G>C	p.Val22Leu	missense	Exon 4 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1839 AN: 152172 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00299 AC: 590 AN: 197048 AF XY: 0.00208

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000693

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00119 AC: 1696 AN: 1430538 Hom.: 41 Cov.: 32 AF XY: 0.00106 AC XY: 749 AN XY: 709466

African (AFR) AF: 0.0426 AC: 1420 AN: 33298

American (AMR) AF: 0.00195 AC: 78 AN: 39956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38678

South Asian (SAS) AF: 0.000157 AC: 13 AN: 82642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46346

Middle Eastern (MID) AF: 0.00266 AC: 15 AN: 5646

European-Non Finnish (NFE) AF: 0.0000200 AC: 22 AN: 1099112

Other (OTH) AF: 0.00249 AC: 148 AN: 59322

GnomAD4 genome AF: 0.0121 AC: 1846 AN: 152290 Hom.: 41 Cov.: 32 AF XY: 0.0116 AC XY: 860 AN XY: 74454

African (AFR) AF: 0.0428 AC: 1779 AN: 41552

American (AMR) AF: 0.00268 AC: 41 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00410 Hom.: 7

Bravo AF: 0.0138

ESP6500AA AF: 0.0449 AC: 197

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00339 AC: 406

Asia WGS AF: 0.00318 AC: 11 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)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 (1)
-	-	1	Mucolipidosis type IV (1)
-	-	1	not specified (1)
-	-	1	Spastic Paraplegia, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.9
DANN	Benign	0.71
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.025
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.33		Loss of sheet (P = 0.007)
MVP		0.081
MPC		1.1
ClinPred		0.0021	T
GERP RS		-2.9
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.48
Mutation Taster		=99/1	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: rs112732576; hg19: chr19-7600855;