rs6733871

Variant names:

• chr2-80302831-T-C
• rs6733871
• NM_178839.5:c.989A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178839.5(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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N330I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7343 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37962 hom.)
• Consequence: LRRTM1 NM_178839.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 29 publications found

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]

CTNNA2 Gene-Disease associations (from GenCC):

• cortical dysplasia, complex, with other brain malformations 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178839.5. 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
	LRRTM1	NM_178839.5	MANE Select	c.989A>G	p.Asn330Ser	missense	Exon 2 of 2	NP_849161.2	Q86UE6
	CTNNA2	NM_001282597.3	MANE Select	c.1057-90380T>C		intron	N/A	NP_001269526.1	P26232-1
	CTNNA2	NM_001282598.2		c.1159-90380T>C		intron	N/A	NP_001269527.1	P26232-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRTM1	ENST00000295057.4	TSL:1 MANE Select	c.989A>G	p.Asn330Ser	missense	Exon 2 of 2	ENSP00000295057.3	Q86UE6
	CTNNA2	ENST00000402739.9	TSL:1 MANE Select	c.1057-90380T>C		intron	N/A	ENSP00000384638.4	P26232-1
	CTNNA2	ENST00000496558.5	TSL:1	c.1057-90380T>C		intron	N/A	ENSP00000419295.1	P26232-2

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

GnomAD2 exomes AF: 0.267 AC: 66665 AN: 250068 AF XY: 0.258

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 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

African (AFR) AF: 0.455 AC: 15231 AN: 33472

American (AMR) AF: 0.366 AC: 16354 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4141 AN: 26136

East Asian (EAS) AF: 0.542 AC: 21500 AN: 39684

South Asian (SAS) AF: 0.278 AC: 23942 AN: 86240

European-Finnish (FIN) AF: 0.231 AC: 12295 AN: 53282

Middle Eastern (MID) AF: 0.253 AC: 1461 AN: 5768

European-Non Finnish (NFE) AF: 0.179 AC: 198949 AN: 1111924

Other (OTH) AF: 0.231 AC: 13950 AN: 60388

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

African (AFR) AF: 0.451 AC: 18705 AN: 41482

American (AMR) AF: 0.291 AC: 4455 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3472

East Asian (EAS) AF: 0.485 AC: 2495 AN: 5140

South Asian (SAS) AF: 0.284 AC: 1368 AN: 4822

European-Finnish (FIN) AF: 0.238 AC: 2520 AN: 10582

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12560 AN: 68004

Other (OTH) AF: 0.259 AC: 546 AN: 2112

Alfa AF: 0.219 Hom.: 17292

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 v4.9

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
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
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.22
Sift	Benign	0.43	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.022
ClinPred		0.0013	T
GERP RS		3.5
Varity_R		0.078
gMVP		0.064
Mutation Taster		=100/0	polymorphism (auto)

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