Genetic Variant LNPK:p.Ser258Ser (chr2-175941013-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001305009.1(LNPK):c.774G>A(p.Ser258Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 453,078 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

LNPK
NM_001305009.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.36

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 2-175941013-C-T is Benign according to our data. Variant chr2-175941013-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2651553.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000836 (127/151914) while in subpopulation NFE AF= 0.000913 (62/67944). AF 95% confidence interval is 0.00073. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LNPK	NM_030650.3 link	c.707-1356G>A		intron_variant	Intron 9 of 12	ENST00000272748.9	NP_085153.1	Q9C0E8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LNPK	ENST00000544803.5 link	c.774G>A	p.Ser258Ser	synonymous_variant	Exon 10 of 14	1		ENSP00000440905.1	Q9C0E8-4
LNPK	ENST00000272748.9 link	c.707-1356G>A		intron_variant	Intron 9 of 12	1	NM_030650.3	ENSP00000272748.4	Q9C0E8-1
LNPK	ENST00000409660.5 link	c.338-1356G>A		intron_variant	Intron 7 of 10	1		ENSP00000386237.1	Q9C0E8-3
LNPK	ENST00000431754.1 link	n.32-1356G>A		intron_variant	Intron 1 of 3	5		ENSP00000388507.1	H7BZA1

Frequencies

GnomAD3 genomes

AF:

0.000837

AC:

127

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00147

AC:

184

AN:

125036

Hom.:

AF XY:

0.00147

AC XY:

101

AN XY:

68580

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000334

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000452

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000935

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.00108

AC:

325

AN:

301164

Hom.:

Cov.:

AF XY:

0.000990

AC XY:

170

AN XY:

171694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000334

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000793

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.000836

AC:

127

AN:

151914

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000913

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.000918

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LNPK: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.40

DANN

Benign

0.39

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