2-175941084-C-CA

Variant names:

• chr2-175941084-C-CA
• rs544134783
• NM_030650.3:c.707-1428dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001305009.1(LNPK):​c.707-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 373,318 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0045 (0 hom.)
• Consequence: LNPK NM_001305009.1 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-175941084-C-CA is Benign according to our data. Variant chr2-175941084-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 3056562.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000327 (49/149770) while in subpopulation SAS AF = 0.000638 (3/4702). AF 95% confidence interval is 0.000209. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.707-1428dupT		intron	N/A	NP_085153.1	Q9C0E8-1
	LNPK	NM_001305008.1		c.905-1428dupT		intron	N/A	NP_001291937.1	Q9C0E8
	LNPK	NM_001305009.1		c.707-5dupT		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_707-1427insT		intron	N/A	ENSP00000272748.4	Q9C0E8-1
	LNPK	ENST00000544803.5	TSL:1	c.707-5_707-4insT		splice_region intron	N/A	ENSP00000440905.1	Q9C0E8-4
	LNPK	ENST00000409660.5	TSL:1	c.338-1428_338-1427insT		intron	N/A	ENSP00000386237.1	Q9C0E8-3

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 47 AN: 149686 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.000705

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.0114 AC: 466 AN: 40706 AF XY: 0.0111

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00997

Gnomad EAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00657

GnomAD4 exome AF: 0.00454 AC: 1014 AN: 223548 Hom.: 0 Cov.: 0 AF XY: 0.00453 AC XY: 582 AN XY: 128574

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

African (AFR) AF: 0.00726 AC: 31 AN: 4272

American (AMR) AF: 0.00587 AC: 86 AN: 14660

Ashkenazi Jewish (ASJ) AF: 0.00477 AC: 35 AN: 7344

East Asian (EAS) AF: 0.00820 AC: 52 AN: 6344

South Asian (SAS) AF: 0.00383 AC: 178 AN: 46502

European-Finnish (FIN) AF: 0.00342 AC: 35 AN: 10220

Middle Eastern (MID) AF: 0.000912 AC: 2 AN: 2194

European-Non Finnish (NFE) AF: 0.00447 AC: 544 AN: 121632

Other (OTH) AF: 0.00491 AC: 51 AN: 10380

⚠️ 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 AF: 0.000327 AC: 49 AN: 149770 Hom.: 0 Cov.: 31 AF XY: 0.000342 AC XY: 25 AN XY: 73088

African (AFR) AF: 0.000318 AC: 13 AN: 40934

American (AMR) AF: 0.000199 AC: 3 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5092

South Asian (SAS) AF: 0.000638 AC: 3 AN: 4702

European-Finnish (FIN) AF: 0.000705 AC: 7 AN: 9928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000312 AC: 21 AN: 67344

Other (OTH) AF: 0.000483 AC: 1 AN: 2070

Alfa AF: 0.00553 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LNPK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs544134783; hg19: chr2-176805812;