2-175941084-CAA-CAAAA

Variant names:

• chr2-175941084-C-CAA
• rs544134783
• NM_030650.3:c.707-1429_707-1428dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001305009.1(LNPK):​c.707-6_707-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 227,400 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LNPK NM_001305009.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LNPK	NM_030650.3	MANE Select	c.707-1429_707-1428dupTT		intron	N/A	NP_085153.1	Q9C0E8-1
	LNPK	NM_001305008.1		c.905-1429_905-1428dupTT		intron	N/A	NP_001291937.1	Q9C0E8
	LNPK	NM_001305009.1		c.707-6_707-5dupTT		splice_region 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.707-1428_707-1427insTT		intron	N/A	ENSP00000272748.4	Q9C0E8-1
	LNPK	ENST00000544803.5	TSL:1	c.707-5_707-4insTT		splice_region intron	N/A	ENSP00000440905.1	Q9C0E8-4
	LNPK	ENST00000409660.5	TSL:1	c.338-1428_338-1427insTT		intron	N/A	ENSP00000386237.1	Q9C0E8-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000737 AC: 3 AN: 40706 AF XY: 0.0000436

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.000141

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000319

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 3 AN: 227400 Hom.: 0 Cov.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4350

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7456

East Asian (EAS) AF: 0.000155 AC: 1 AN: 6450

South Asian (SAS) AF: 0.00 AC: 0 AN: 47308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2202

European-Non Finnish (NFE) AF: 0.0000162 AC: 2 AN: 123792

Other (OTH) AF: 0.00 AC: 0 AN: 10542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47

Splicing

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

Other links and lift over

dbSNP: rs544134783; hg19: chr2-176805812;