rs2239796

Variant names:

• chr6-36293137-C-T
• rs2239796
• NM_001374623.1:c.504+11C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374623.1(PNPLA1):​c.504+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,612,660 control chromosomes in the GnomAD database, including 80,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6015 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74939 hom.)
• Consequence: PNPLA1 NM_001374623.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.29

Genes affected

PNPLA1 (HGNC:21246): (patatin like phospholipase domain containing 1) The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-36293137-C-T is Benign according to our data. Variant chr6-36293137-C-T is described in ClinVar as [Benign]. Clinvar id is 257573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36293137-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.504+11C>T		intron_variant	Intron 3 of 8	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.504+11C>T		intron_variant	Intron 3 of 8	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.507+11C>T		intron_variant	Intron 3 of 7	1		ENSP00000391868.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38192 AN: 151966 Hom.: 6002 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.320 AC: 80234 AN: 250984 Hom.: 14667 AF XY: 0.314 AC XY: 42596 AN XY: 135654

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.262

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.313 AC: 456477 AN: 1460574 Hom.: 74939 Cov.: 37 AF XY: 0.310 AC XY: 224948 AN XY: 726670

Gnomad4 AFR exome AF: 0.0501

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.376

Gnomad4 NFE exome AF: 0.318

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.251 AC: 38207 AN: 152086 Hom.: 6015 Cov.: 32 AF XY: 0.256 AC XY: 19059 AN XY: 74344

Gnomad4 AFR AF: 0.0645

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.207

Alfa AF: 0.292 Hom.: 5723

Bravo AF: 0.242

Asia WGS AF: 0.212 AC: 736 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.84
CADD	Benign	0.11
DANN	Benign	0.43

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: rs2239796; hg19: chr6-36260914; COSMIC: COSV57233262;