Genetic Variant SLC12A4:c.*880_*893dupCCCGTCATCCTCGG (chr16-67943946-A-ACCGAGGATGACGGG) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000229.2(LCAT):c.142_154+1dupCCCGTCATCCTCGG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000718 in 1,393,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

LCAT
NM_000229.2 splice_donor, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.82

Variant links:

Genes affected

SLC12A4 (HGNC:10913): (solute carrier family 12 member 4) This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

SLC12A4 links:

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

LCAT links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-67943946-A-ACCGAGGATGACGGG is Pathogenic according to our data. Variant chr16-67943946-A-ACCGAGGATGACGGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3581217.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A4	NM_005072.5 link	c.880_893dupCCCGTCATCCTCGG		3_prime_UTR_variant	Exon 24 of 24	ENST00000316341.8	NP_005063.1	Q9UP95-1
LCAT	NM_000229.2 link	c.142_154+1dupCCCGTCATCCTCGG		splice_donor_variant, intron_variant	Intron 1 of 5	ENST00000264005.10	NP_000220.1	P04180A0A140VK24

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A4	ENST00000316341 link	c.880_893dupCCCGTCATCCTCGG	3_prime_UTR_variant	Exon 24 of 24	1	NM_005072.5	ENSP00000318557.3	Q9UP95-1
LCAT	ENST00000264005.10 link	c.142_154+1dupCCCGTCATCCTCGG	splice_donor_variant, intron_variant	Intron 1 of 5	1	NM_000229.2	ENSP00000264005.5	P04180
LCAT	ENST00000575467.5 link	n.142_154+1dupCCCGTCATCCTCGG	splice_donor_variant, intron_variant	Intron 1 of 5	5		ENSP00000460653.1	I3L3R0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

AF XY:

0.00

AC XY:

AN XY:

80016

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000886

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1393084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000281

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Norum disease;C0342895:Fish-eye disease

Pathogenic:1

Feb 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over