2-175939622-T-C

Position:

• chr2-175939622-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_030650.3(LNPK):​c.742A>G​(p.Ile248Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,606,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: LNPK NM_030650.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.39

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017902076).
• BP6: Variant 2-175939622-T-C is Benign according to our data. Variant chr2-175939622-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3119475.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000296 (45/152080) while in subpopulation SAS AF= 0.000627 (3/4782). AF 95% confidence interval is 0.000293. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LNPK	NM_030650.3	c.742A>G	p.Ile248Val	missense_variant	10/13	ENST00000272748.9	NP_085153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LNPK	ENST00000272748.9	c.742A>G	p.Ile248Val	missense_variant	10/13	1	NM_030650.3	ENSP00000272748.4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151962 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000585 AC: 146 AN: 249722 Hom.: 0 AF XY: 0.000711 AC XY: 96 AN XY: 134996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000849

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000411 AC: 598 AN: 1454092 Hom.: 0 Cov.: 27 AF XY: 0.000473 AC XY: 342 AN XY: 723780

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000782

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152080 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000627

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000489 Hom.: 1

Bravo AF: 0.000446

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.742A>G (p.I248V) alteration is located in exon 10 (coding exon 9) of the LNPK gene. This alteration results from a A to G substitution at nucleotide position 742, causing the isoleucine (I) at amino acid position 248 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

LNPK: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0080	B;.;.
Vest4		0.099
MVP		0.33
MPC		0.12
ClinPred		0.019	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs201848822; hg19: chr2-176804350;