2-175964387-C-T

Position:

chr2-175964387-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000272748.9(LNPK):c.478G>A(p.Ala160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

LNPK
ENST00000272748.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.135

Variant links:

Genes affected

LNPK (HGNC:21610): (lunapark, ER junction formation factor) Enables identical protein binding activity. Involved in endoplasmic reticulum tubular network maintenance and positive regulation of endoplasmic reticulum tubular network organization. Located in endoplasmic reticulum tubular network membrane and nucleoplasm. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

LNPK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058559).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000112 (17/152266) while in subpopulation AMR AF= 0.000392 (6/15290). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LNPK	NM_030650.3 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	8/13	ENST00000272748.9	NP_085153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LNPK	ENST00000272748.9 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	8/13	1	NM_030650.3	ENSP00000272748	P1	Q9C0E8-1
LNPK	ENST00000544803.5 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	8/14	1		ENSP00000440905		Q9C0E8-4
LNPK	ENST00000409660.5 linkuse as main transcript	c.109G>A	p.Ala37Thr	missense_variant	6/11	1		ENSP00000386237		Q9C0E8-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000116

AC:

AN:

251066

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1460938

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000425

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:

0.0000342

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000112

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

The c.478G>A (p.A160T) alteration is located in exon 8 (coding exon 7) of the LNPK gene. This alteration results from a G to A substitution at nucleotide position 478, causing the alanine (A) at amino acid position 160 to be replaced by a threonine (T). 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

0.074

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.055

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0059

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;N;.

MutationTaster

Benign

0.76

D;D;D;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.55

N;N;N

REVEL

Benign

0.083

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.12

MutPred

0.18

Gain of glycosylation at A160 (P = 0.008);Gain of glycosylation at A160 (P = 0.008);.;

MVP

0.30

MPC

0.13

ClinPred

0.024

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.26

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

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