Genetic Variant NM_178839.5:c.989A>G (chr2-80302831-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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.

Frequency

Genomes: 𝑓 0.29 ( 7343 hom., cov: 32)

Exomes 𝑓: 0.21 ( 37962 hom. )

Consequence

LRRTM1
NM_178839.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.21

Publications

29 publications found

Variant links:

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]

LRRTM1 links:

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

CTNNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM1	NM_178839.5 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 2 of 2	ENST00000295057.4	NP_849161.2	Q86UE6
CTNNA2	NM_001282597.3 link	c.1057-90380T>C		intron_variant	Intron 7 of 18	ENST00000402739.9	NP_001269526.1	P26232-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRTM1	ENST00000295057.4 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 2 of 2	1	NM_178839.5	ENSP00000295057.3		Q86UE6
CTNNA2	ENST00000402739.9 link	c.1057-90380T>C		intron_variant	Intron 7 of 18	1	NM_001282597.3	ENSP00000384638.4		P26232-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43417

AN:

151996

Hom.:

7319

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.211

AC XY:

153730

AN XY:

727078

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

16210

32420

48631

64841

81051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7316

14632

21948

29264

36580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.286

AC:

43497

AN:

152114

Hom.:

7343

Cov.:

AF XY:

0.290

AC XY:

21560

AN XY:

74370

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12560

AN:

68004

Other (OTH)

AF:

0.259

AC:

546

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1533

3065

4598

6130

7663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.63

.;T

MetaRNN

Benign

0.00050

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.1

N;N

PhyloP100

2.2

PrimateAI

Uncertain

0.59

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

GERP RS

3.5

Varity_R

0.078

gMVP

0.064

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over