12-1828174-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001039029.3(LRTM2):c.26G>A(p.Gly9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,546,704 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: LRTM2 NM_001039029.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.00

Genes affected

LRTM2 (HGNC:32443): (leucine rich repeats and transmembrane domains 2) Predicted to enable Roundabout binding activity and heparin binding activity. Predicted to be involved in axon guidance and negative chemotaxis. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072345436).
• BP6: Variant 12-1828174-G-A is Benign according to our data. Variant chr12-1828174-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2368694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRTM2	NM_001039029.3	c.26G>A	p.Gly9Glu	missense_variant	3/5	ENST00000299194.6
CACNA2D4	NM_172364.5	c.2551+12565C>T		intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRTM2	ENST00000299194.6	c.26G>A	p.Gly9Glu	missense_variant	3/5	2	NM_001039029.3	P1
CACNA2D4	ENST00000382722.10	c.2551+12565C>T		intron_variant		1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000433 AC: 63 AN: 145558 Hom.: 1 AF XY: 0.000413 AC XY: 32 AN XY: 77532

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000448

Gnomad FIN exome AF: 0.000264

Gnomad NFE exome AF: 0.000875

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.00109 AC: 1523 AN: 1394350 Hom.: 1 Cov.: 31 AF XY: 0.00109 AC XY: 749 AN XY: 687660

Gnomad4 AFR exome AF: 0.000287

Gnomad4 AMR exome AF: 0.000340

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000762

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000416 AC XY: 31 AN XY: 74510

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000518

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.000983 AC: 7

ExAC AF: 0.000212 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.72
DEOGEN2	Benign	0.010	T;T;T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.034	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.25	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.072
MVP		0.48
MPC		0.39
ClinPred		0.0010	T
GERP RS		3.2
Varity_R		0.029
gMVP		0.40

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: rs186004852; hg19: chr12-1937340;