rs6733871

Positions:

• chr2-80302831-T-C
• chr2-80302831-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000295057.4(LRRTM1):​c.989A>G​(p.Asn330Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,676 control chromosomes in the GnomAD database, including 45,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7343 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37962 hom.)
• Consequence: LRRTM1 ENST00000295057.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

Genes affected

LRRTM1 (HGNC:19408): (leucine rich repeat transmembrane neuronal 1) Predicted to be involved in regulation of postsynaptic density assembly and regulation of presynapse 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. Located in endoplasmic reticulum and growth cone. Is active in GABA-ergic synapse. Is integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

CTNNA2 (HGNC:2510): (catenin alpha 2) Enables actin filament binding activity. Involved in negative regulation of Arp2/3 complex-mediated actin nucleation; regulation of neuron migration; and regulation of neuron projection development. Located in cytoplasm. Implicated in complex cortical dysplasia with other brain malformations. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.018711E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRTM1	NM_178839.5	c.989A>G	p.Asn330Ser	missense_variant	2/2	ENST00000295057.4	NP_849161.2
CTNNA2	NM_001282597.3	c.1057-90380T>C		intron_variant		ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRTM1	ENST00000295057.4	c.989A>G	p.Asn330Ser	missense_variant	2/2	1	NM_178839.5	ENSP00000295057	P1
CTNNA2	ENST00000402739.9	c.1057-90380T>C		intron_variant		1	NM_001282597.3	ENSP00000384638

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43417 AN: 151996 Hom.: 7319 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.267 AC: 66665 AN: 250068 Hom.: 10398 AF XY: 0.258 AC XY: 34992 AN XY: 135372

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.485

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.211 AC: 307823 AN: 1461562 Hom.: 37962 Cov.: 33 AF XY: 0.211 AC XY: 153730 AN XY: 727078

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.542

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.286 AC: 43497 AN: 152114 Hom.: 7343 Cov.: 32 AF XY: 0.290 AC XY: 21560 AN XY: 74370

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.259

Alfa AF: 0.209 Hom.: 7809

Bravo AF: 0.298

TwinsUK AF: 0.187 AC: 695

ALSPAC AF: 0.171 AC: 660

ESP6500AA AF: 0.450 AC: 1982

ESP6500EA AF: 0.178 AC: 1535

ExAC AF: 0.266 AC: 32338

Asia WGS AF: 0.390 AC: 1355 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.63	.;T
MetaRNN	Benign	0.00050	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N;N
MutationTaster	Benign	2.7e-15	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.22
Sift	Benign	0.43	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	B;B
Vest4		0.022
ClinPred		0.0013	T
GERP RS		3.5
Varity_R		0.078
gMVP		0.064

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: rs6733871; hg19: chr2-80529956; COSMIC: COSV54438456; COSMIC: COSV54438456;