NM_002341.2:c.228G>C

Variant names:

• chr6-31581611-C-G
• rs544081396
• NM_002341.2:c.228G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002341.2(LTB):​c.228G>C​(p.Glu76Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E76E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTB NM_002341.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.645
• Publications: 0 publications found

Genes affected

LTB (HGNC:6711): (lymphotoxin beta) Lymphotoxin beta is a type II membrane protein of the TNF family. It anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. The predominant form on the lymphocyte surface is the lymphotoxin-alpha 1/beta 2 complex (e.g. 1 molecule alpha/2 molecules beta) and this complex is the primary ligand for the lymphotoxin-beta receptor. The minor complex is lymphotoxin-alpha 2/beta 1. LTB is an inducer of the inflammatory response system and involved in normal development of lymphoid tissue. Lymphotoxin-beta isoform b is unable to complex with lymphotoxin-alpha suggesting a function for lymphotoxin-beta which is independent of lympyhotoxin-alpha. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08981383).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002341.2. 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
	LTB	NM_002341.2	MANE Select	c.228G>C	p.Glu76Asp	missense	Exon 3 of 4	NP_002332.1	Q5STB2
	LTB	NM_009588.1		c.182G>C	p.Arg61Thr	missense	Exon 2 of 3	NP_033666.1	Q06643-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTB	ENST00000429299.3	TSL:1 MANE Select	c.228G>C	p.Glu76Asp	missense	Exon 3 of 4	ENSP00000410481.3	Q06643-1
	LTB	ENST00000446745.2	TSL:1	c.182G>C	p.Arg61Thr	missense	Exon 2 of 3	ENSP00000416113.2	Q06643-2
	LTB	ENST00000482429.1	TSL:2	n.796G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246552 AF XY: 0.00000744

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: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460748 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.65
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.019
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.18	B
Vest4		0.35
MutPred		0.27		Loss of methylation at K73 (P = 0.0924)
MVP		0.34
MPC		0.24
ClinPred		0.65	D
GERP RS		2.6
Varity_R		0.061
gMVP		0.24
Mutation Taster		=98/2	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: rs544081396; hg19: chr6-31549388; COSMIC: COSV105316672;