rs1553498948

Variant names:

• chr2-175939637-GT-G
• rs1553498948
• NM_030650.3:c.726delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_030650.3(LNPK):​c.726delA​(p.Pro243LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LNPK NM_030650.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.74
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-175939637-GT-G is Pathogenic according to our data. Variant chr2-175939637-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 559606.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030650.3. 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
	LNPK	NM_030650.3	MANE Select	c.726delA	p.Pro243LeufsTer2	frameshift	Exon 10 of 13	NP_085153.1	Q9C0E8-1
	LNPK	NM_001305008.1		c.924delA	p.Pro309LeufsTer2	frameshift	Exon 10 of 13	NP_001291937.1	Q9C0E8
	LNPK	NM_001305009.1		c.819delA	p.Pro274LeufsTer2	frameshift	Exon 11 of 14	NP_001291938.1	Q9C0E8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LNPK	ENST00000272748.9	TSL:1 MANE Select	c.726delA	p.Pro243LeufsTer2	frameshift	Exon 10 of 13	ENSP00000272748.4	Q9C0E8-1
	LNPK	ENST00000544803.5	TSL:1	c.819delA	p.Pro274LeufsTer2	frameshift	Exon 11 of 14	ENSP00000440905.1	Q9C0E8-4
	LNPK	ENST00000409660.5	TSL:1	c.357delA	p.Pro120LeufsTer2	frameshift	Exon 8 of 11	ENSP00000386237.1	Q9C0E8-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553498948;

hg19: chr2-176804365;