NM_207510.4:c.248C>A

Variant names:

• chr9-136984764-C-A
• rs199948531
• NM_207510.4:c.248C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207510.4(LCNL1):​c.248C>A​(p.Ala83Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A83V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: LCNL1 NM_207510.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

Genes affected

LCNL1 (HGNC:34436): (lipocalin like 1) Predicted to enable small molecule binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000284341 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207510.4. 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
	LCNL1	NM_207510.4	MANE Select	c.248C>A	p.Ala83Asp	missense	Exon 3 of 3	NP_997393.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCNL1	ENST00000408973.3	TSL:2 MANE Select	c.248C>A	p.Ala83Asp	missense	Exon 3 of 3	ENSP00000386162.2	Q6ZST4
	LCNL1	ENST00000460177.1	TSL:1	n.1240+201C>A		intron	N/A
	ENSG00000284341	ENST00000471521.5	TSL:5	n.*214+201C>A		intron	N/A	ENSP00000435033.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406544 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 693200

⚠️ 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: 31754

American (AMR) AF: 0.00 AC: 0 AN: 39750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23016

East Asian (EAS) AF: 0.00 AC: 0 AN: 37776

South Asian (SAS) AF: 0.00 AC: 0 AN: 79378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079998

Other (OTH) AF: 0.00 AC: 0 AN: 57828

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.79		Gain of phosphorylation at Y86 (P = 0.0815)
MVP		0.13
MPC		0.90
ClinPred		0.91	D
GERP RS		3.3
Varity_R		0.60
gMVP		0.86
Mutation Taster		=88/12	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: rs199948531; hg19: chr9-139879216;