5-138874307-C-T

Variant names:

• chr5-138874307-C-T
• rs776129690
• NM_015564.3:c.254G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015564.3(LRRTM2):​c.254G>A​(p.Ser85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRTM2 NM_015564.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18045115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM2	NM_015564.3	c.254G>A	p.Ser85Asn	missense_variant	Exon 2 of 2	ENST00000274711.7	NP_056379.1
CTNNA1	NM_001903.5	c.1063-11905C>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.254G>A	p.Ser85Asn	missense_variant	Exon 2 of 2	1	NM_015564.3	ENSP00000274711.5
CTNNA1	ENST00000302763.12	c.1063-11905C>T		intron_variant	Intron 7 of 17	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.96	L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.84	P
Vest4		0.39
MutPred		0.29		Loss of sheet (P = 0.0817);
MVP		0.13
MPC		0.95
ClinPred		0.50	T
GERP RS		5.3
Varity_R		0.34
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs776129690; hg19: chr5-138209996;