NM_000229.2:c.118G>C

Variant names:

• chr16-67943984-C-G
• NM_000229.2:c.118G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000229.2(LCAT):​c.118G>C​(p.Ala40Pro) 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 1,396,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A40S) 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: 2.35
• 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 3 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, 7 uncertain in NM_000229.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33855158).

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.118G>C	p.Ala40Pro	missense	Exon 1 of 6	NP_000220.1	P04180
	SLC12A4	NM_005072.5	MANE Select	c.*856G>C		3_prime_UTR	Exon 24 of 24	NP_005063.1	Q9UP95-1
	SLC12A4	NM_001145962.1		c.*856G>C		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.118G>C	p.Ala40Pro	missense	Exon 1 of 6	ENSP00000264005.5	P04180
	SLC12A4	ENST00000316341.8	TSL:1 MANE Select	c.*856G>C		3_prime_UTR	Exon 24 of 24	ENSP00000318557.3	Q9UP95-1
	LCAT	ENST00000575467.5	TSL:5	n.118G>C		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: 1396164 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688458

African (AFR) AF: 0.00 AC: 0 AN: 31558

American (AMR) AF: 0.00 AC: 0 AN: 35580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35694

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5012

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077698

Other (OTH) AF: 0.00 AC: 0 AN: 57790

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.23
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.97
MPC		1.2
ClinPred		0.82	D
GERP RS		5.1
PromoterAI		-0.020	Neutral
Varity_R		0.54
gMVP		0.70
Mutation Taster		=57/43	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

hg19: chr16-67977887;