chr2-175937343-C-G

Variant names:

• chr2-175937343-C-G
• rs1684599962
• NM_030650.3:c.1054+1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_030650.3(LNPK):​c.1054+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LNPK NM_030650.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.55
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13286713 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-175937343-C-G is Pathogenic according to our data. Variant chr2-175937343-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1028894.Status of the report is criteria_provided_single_submitter, 1 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.1054+1G>C		splice_donor intron	N/A	NP_085153.1	Q9C0E8-1
	LNPK	NM_001305008.1		c.1252+1G>C		splice_donor intron	N/A	NP_001291937.1	Q9C0E8
	LNPK	NM_001305009.1		c.1147+1G>C		splice_donor intron	N/A	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.1054+1G>C		splice_donor intron	N/A	ENSP00000272748.4	Q9C0E8-1
	LNPK	ENST00000544803.5	TSL:1	c.1147+1G>C		splice_donor intron	N/A	ENSP00000440905.1	Q9C0E8-4
	LNPK	ENST00000409660.5	TSL:1	c.685+1G>C		splice_donor intron	N/A	ENSP00000386237.1	Q9C0E8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.5
GERP RS		5.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1684599962; hg19: chr2-176802071;