ENST00000221249:c.-214C>T

Variant names:

• chr19-7534221-C-T
• rs141371215
• ENST00000221249.10:c.-214C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000221249.10(PNPLA6):​c.-214C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 328,042 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: PNPLA6 ENST00000221249.10 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0440
• 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]

ENSG00000268614 (HGNC:):

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MCOLN1 Gene-Disease associations (from GenCC):

• mucolipidosis type IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-7534221-C-T is Benign according to our data. Variant chr19-7534221-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369303.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 = 0.0146 (2223/152314) while in subpopulation AFR AF = 0.0512 (2127/41560). AF 95% confidence interval is 0.0494. There are 54 homozygotes in GnomAd4. There are 1034 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000221249.10. 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_006702.5		c.-214C>T		5_prime_UTR	Exon 1 of 35	NP_006693.3
	MCOLN1	NM_020533.3	MANE Select	c.*426C>T		downstream_gene	N/A	NP_065394.1	Q9GZU1
	PNPLA6	NM_001166112.2		c.-421C>T		upstream_gene	N/A	NP_001159584.1	Q8IY17-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000221249.10	TSL:1	c.-214C>T		5_prime_UTR	Exon 1 of 35	ENSP00000221249.5	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*132C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000471492.1	M0R0W3
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*132C>T		3_prime_UTR	Exon 3 of 10	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2212 AN: 152196 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00153 AC: 269 AN: 175728 Hom.: 4 Cov.: 0 AF XY: 0.00119 AC XY: 113 AN XY: 95028

African (AFR) AF: 0.0427 AC: 216 AN: 5064

American (AMR) AF: 0.00337 AC: 20 AN: 5932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4398

East Asian (EAS) AF: 0.00 AC: 0 AN: 6582

South Asian (SAS) AF: 0.000246 AC: 8 AN: 32496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 632

European-Non Finnish (NFE) AF: 0.0000966 AC: 10 AN: 103570

Other (OTH) AF: 0.00171 AC: 15 AN: 8748

GnomAD4 genome AF: 0.0146 AC: 2223 AN: 152314 Hom.: 54 Cov.: 32 AF XY: 0.0139 AC XY: 1034 AN XY: 74484

African (AFR) AF: 0.0512 AC: 2127 AN: 41560

American (AMR) AF: 0.00425 AC: 65 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68028

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

Alfa AF: 0.0110 Hom.: 6

Bravo AF: 0.0162

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 39 (1)
-	-	1	Mucolipidosis type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.044
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs141371215; hg19: chr19-7599107;