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

Variant summary

Our verdict is Benign. The variant received -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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

LNPK links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305009.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LNPK	NM_030650.3	MANE Select	c.707-1356G>A		intron	N/A	NP_085153.1	Q9C0E8-1
LNPK	NM_001305009.1		c.774G>A	p.Ser258Ser	synonymous	Exon 10 of 14	NP_001291938.1	Q9C0E8-4
LNPK	NM_001305008.1		c.905-1356G>A		intron	N/A	NP_001291937.1	Q9C0E8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LNPK	ENST00000544803.5	TSL:1	c.774G>A	p.Ser258Ser	synonymous	Exon 10 of 14	ENSP00000440905.1	Q9C0E8-4
LNPK	ENST00000272748.9	TSL:1 MANE Select	c.707-1356G>A		intron	N/A	ENSP00000272748.4	Q9C0E8-1
LNPK	ENST00000409660.5	TSL:1	c.338-1356G>A		intron	N/A	ENSP00000386237.1	Q9C0E8-3

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

GnomAD2 exomes

AF:

0.00147

AC:

184

AN:

125036

AF XY:

0.00147

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 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

African (AFR)

AF:

0.00

AC:

AN:

8312

American (AMR)

AF:

0.000334

AC:

AN:

26956

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

164

AN:

10702

East Asian (EAS)

AF:

0.00

AC:

AN:

8910

South Asian (SAS)

AF:

0.00

AC:

AN:

59480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2760

European-Non Finnish (NFE)

AF:

0.000793

AC:

125

AN:

157654

Other (OTH)

AF:

0.00192

AC:

AN:

14074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000836

AC:

127

AN:

151914

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41454

American (AMR)

AF:

0.000328

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000913

AC:

AN:

67944

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.000918

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.40

(source)

DANN

Benign

0.39

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over