NM_002297.4:c.298G>C

Variant names:

• chr9-135523885-G-C
• rs117638349
• NM_002297.4:c.298G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002297.4(LCN1):​c.298G>C​(p.Gly100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,578 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G100D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (53 hom.)
• Consequence: LCN1 NM_002297.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790
• Publications: 8 publications found

Genes affected

LCN1 (HGNC:6525): (lipocalin 1) This gene encodes a member of the lipocalin family of small secretory proteins. Lipocalins are extracellular transport proteins that bind to a variety of hydrophobic ligands. The encoded protein is the primary lipid binding protein in tears and is overproduced in response to multiple stimuli including infection and stress. The encoded protein may be a marker for chromosome aneuploidy as well as an autoantigen in Sjogren's syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and two pseudogenes of this gene are also located on the long arm of chromosome 9. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067055225).
• BP6: Variant 9-135523885-G-C is Benign according to our data. Variant chr9-135523885-G-C is described in ClinVar as Benign. ClinVar VariationId is 711321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002297.4. 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
	LCN1	NM_002297.4	MANE Select	c.298G>C	p.Gly100Arg	missense	Exon 4 of 7	NP_002288.1	P31025
	LCN1	NM_001252618.2		c.298G>C	p.Gly100Arg	missense	Exon 4 of 7	NP_001239547.1
	LCN1	NM_001252619.2		c.298G>C	p.Gly100Arg	missense	Exon 4 of 7	NP_001239548.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCN1	ENST00000371781.4	TSL:1 MANE Select	c.298G>C	p.Gly100Arg	missense	Exon 4 of 7	ENSP00000360846.3	P31025
	LCN1	ENST00000263598.6	TSL:1	c.298G>C	p.Gly100Arg	missense	Exon 4 of 7	ENSP00000263598.2	P31025

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152150 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00529 AC: 1329 AN: 251336 AF XY: 0.00534

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.00794

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00731 AC: 10676 AN: 1461310 Hom.: 53 Cov.: 31 AF XY: 0.00718 AC XY: 5219 AN XY: 726972

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.00586 AC: 262 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86242

European-Finnish (FIN) AF: 0.00389 AC: 208 AN: 53402

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.00858 AC: 9533 AN: 1111512

Other (OTH) AF: 0.00730 AC: 441 AN: 60378

GnomAD4 genome AF: 0.00529 AC: 805 AN: 152268 Hom.: 2 Cov.: 33 AF XY: 0.00522 AC XY: 389 AN XY: 74468

African (AFR) AF: 0.00188 AC: 78 AN: 41542

American (AMR) AF: 0.00765 AC: 117 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00782 AC: 532 AN: 68016

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00694 Hom.: 3

Bravo AF: 0.00566

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00516 AC: 627

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00818

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.079
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.42
MPC		0.42
ClinPred		0.080	T
GERP RS		2.1
Varity_R		0.37
gMVP		0.58
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs117638349; hg19: chr9-138415731;