Genetic Variant LCN6:p.Gly77Arg (chr9-136747425-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198946.3(LCN6):c.229G>C(p.Gly77Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LCN6
NM_198946.3 missense, splice_region

Scores

Splicing: ADA: 0.00002288

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.96

Publications

2 publications found

Variant links:

Genes affected

LCN6 (HGNC:17337): (lipocalin 6) Predicted to enable small molecule binding activity. Predicted to be involved in single fertilization. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

LCN6 links:

ENSG00000204003 (HGNC:):

ENSG00000204003 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042748928).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198946.3. 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
	LCN6	NM_198946.3	MANE Select	c.229G>C	p.Gly77Arg	missense splice_region	Exon 2 of 7	NP_945184.1	P62502
	LOC100128593	NR_033913.1		n.389C>G		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LCN6	ENST00000341206.9	TSL:1 MANE Select	c.229G>C	p.Gly77Arg	missense splice_region	Exon 2 of 7	ENSP00000339621.3	P62502
ENSG00000204003	ENST00000435202.5	TSL:2	n.199G>C		splice_region non_coding_transcript_exon	Exon 2 of 11	ENSP00000399627.1	H7C1C5
LCN6	ENST00000960388.1		c.229G>C	p.Gly77Arg	missense splice_region	Exon 2 of 7	ENSP00000630447.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249838

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460492

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111690

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.65

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0012

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.55

M_CAP

Benign

0.0049

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.76

PhyloP100

-2.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.71

REVEL

Benign

0.038

Sift

Benign

0.90

Sift4G

Benign

0.88

Polyphen

0.020

Vest4

0.11

MutPred

0.39

Gain of solvent accessibility (P = 0.0674)

MVP

0.10

MPC

0.053

ClinPred

0.041

GERP RS

-0.60

Varity_R

0.070

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over