5-138874020-G-T

Variant names:

• chr5-138874020-G-T
• NM_015564.3:c.541C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015564.3(LRRTM2):​c.541C>A​(p.Arg181Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,704 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRTM2 NM_015564.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99

Genes affected

LRRTM2 (HGNC:19409): (leucine rich repeat transmembrane neuronal 2) Predicted to enable neurexin family protein binding activity. Predicted to be involved in regulation of postsynaptic density assembly. Predicted to act upstream of or within several processes, including long-term synaptic potentiation; negative regulation of receptor internalization; and positive regulation of synapse assembly. Is active in GABA-ergic synapse. Is integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

CTNNA1 (HGNC:2509): (catenin alpha 1) This gene encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The encoded mechanosensing protein contains three vinculin homology domains and undergoes conformational changes in response to cytoskeletal tension, resulting in the reconfiguration of cadherin-actin filament connections. Certain mutations in this gene cause butterfly-shaped pigment dystrophy. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM2	NM_015564.3	c.541C>A	p.Arg181Ser	missense_variant	Exon 2 of 2	ENST00000274711.7	NP_056379.1
CTNNA1	NM_001903.5	c.1063-12192G>T		intron_variant	Intron 7 of 17	ENST00000302763.12	NP_001894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRTM2	ENST00000274711.7	c.541C>A	p.Arg181Ser	missense_variant	Exon 2 of 2	1	NM_015564.3	ENSP00000274711.5
CTNNA1	ENST00000302763.12	c.1063-12192G>T		intron_variant	Intron 7 of 17	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.88	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Benign	0.072	T
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.53		Loss of helix (P = 0.079);
MVP		0.20
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-138209709;