rs2058312868

Variant names:

• chr16-67943986-T-A
• rs2058312868
• NM_000229.2:c.116A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-67943986-T-A
• chr16-67943986-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000229.2(LCAT):​c.116A>T​(p.Lys39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K39R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.978
• Publications: 0 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000229.2
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000229.2. 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
	LCAT	NM_000229.2	MANE Select	c.116A>T	p.Lys39Met	missense	Exon 1 of 6	NP_000220.1	P04180
	SLC12A4	NM_005072.5	MANE Select	c.*854A>T		3_prime_UTR	Exon 24 of 24	NP_005063.1	Q9UP95-1
	SLC12A4	NM_001145962.1		c.*854A>T		3_prime_UTR	Exon 23 of 23	NP_001139434.1	Q9UP95-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.116A>T	p.Lys39Met	missense	Exon 1 of 6	ENSP00000264005.5	P04180
	SLC12A4	ENST00000316341.8	TSL:1 MANE Select	c.*854A>T		3_prime_UTR	Exon 24 of 24	ENSP00000318557.3	Q9UP95-1
	LCAT	ENST00000575467.5	TSL:5	n.116A>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000460653.1	I3L3R0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396324 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688572

African (AFR) AF: 0.0000317 AC: 1 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 35586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35688

South Asian (SAS) AF: 0.00 AC: 0 AN: 79008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5040

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077816

Other (OTH) AF: 0.00 AC: 0 AN: 57800

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Norum disease;C0342895:Fish-eye disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.98
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.30		Loss of ubiquitination at K39 (P = 0.0056)
MVP		0.98
MPC		1.1
ClinPred		0.84	D
GERP RS		5.1
PromoterAI		0.0047	Neutral
Varity_R		0.12
gMVP		0.53
Mutation Taster		=61/39	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: rs2058312868; hg19: chr16-67977889;