2-210436296-C-G

Variant names:

• chr2-210436296-C-G
• rs200373437
• NM_006055.3:c.970G>C

Variant summary

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

The NM_006055.3(LANCL1):​c.970G>C​(p.Gly324Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,808 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. G324S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LANCL1 NM_006055.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

LANCL1 (HGNC:6508): (LanC like glutathione S-transferase 1) This gene encodes a loosely associated peripheral membrane protein related to the LanC family of bacterial membrane-associated proteins involved in the biosynthesis of antimicrobial peptides. This protein may play a role as a peptide-modifying enzyme component in eukaryotic cells. Previously considered a member of the G-protein-coupled receptor superfamily, this protein is now in the LanC family. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2008]

LANCL1-AS1 (HGNC:50727): (LANCL1 antisense RNA 1)

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, 0.994

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006055.3. 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
	LANCL1	NM_006055.3	MANE Select	c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	NP_006046.1	O43813
	LANCL1	NM_001136574.2		c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	NP_001130046.1	Q53TN2
	LANCL1	NM_001136575.2		c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	NP_001130047.1	Q53TN2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LANCL1	ENST00000450366.7	TSL:1 MANE Select	c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	ENSP00000393597.2	O43813
	LANCL1	ENST00000233714.8	TSL:1	c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	ENSP00000233714.4	O43813
	LANCL1	ENST00000431941.6	TSL:1	c.970G>C	p.Gly324Arg	missense	Exon 8 of 10	ENSP00000397646.2	O43813

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461808 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of helix (P = 0.1299)
MVP		0.97
MPC		0.045
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.92
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs200373437; hg19: chr2-211301020;