chr13-46134155-T-C

Position:

• chr13-46134155-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002298.5(LCP1):​c.1598A>G​(p.Lys533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. K533E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LCP1 NM_002298.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.150

Genes affected

LCP1 (HGNC:6528): (lymphocyte cytosolic protein 1) Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. Plastin 1 (otherwise known as Fimbrin) is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). However, L-plastin has been found in many types of malignant human cells of non-hemopoietic origin suggesting that its expression is induced accompanying tumorigenesis in solid tissues. [provided by RefSeq, Jul 2008]

CPB2-AS1 (HGNC:39898): (CPB2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.142497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCP1	NM_002298.5	c.1598A>G	p.Lys533Arg	missense_variant	14/16	ENST00000323076.7
LCP1	XM_005266374.3	c.1598A>G	p.Lys533Arg	missense_variant	14/16
LCP1	XM_047430303.1	c.1598A>G	p.Lys533Arg	missense_variant	14/16
LCP1	XM_047430304.1	c.1163A>G	p.Lys388Arg	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCP1	ENST00000323076.7	c.1598A>G	p.Lys533Arg	missense_variant	14/16	1	NM_002298.5	P1
CPB2-AS1	ENST00000663159.1	n.470-17339T>C		intron_variant, non_coding_transcript_variant
LCP1	ENST00000398576.6	c.1598A>G	p.Lys533Arg	missense_variant	17/19	5		P1
LCP1	ENST00000674665.1	c.305A>G	p.Lys102Arg	missense_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461476 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.1598A>G (p.K533R) alteration is located in exon 14 (coding exon 13) of the LCP1 gene. This alteration results from a A to G substitution at nucleotide position 1598, causing the lysine (K) at amino acid position 533 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.7
DANN	Benign	0.89
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.21
Sift	Benign	0.043	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.0	B;B
Vest4		0.049
MutPred		0.39		Loss of ubiquitination at K533 (P = 0.0134);Loss of ubiquitination at K533 (P = 0.0134);
MVP		0.61
MPC		0.29
ClinPred		0.11	T
GERP RS		-5.5
Varity_R		0.099
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-46708290;