rs4765845

chr12-1820792-G-A

Variant summary

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

The NM_001039029.3(LRTM2):c.-281G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,246 control chromosomes in the GnomAD database, including 14,412 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (14404 hom., cov: 33)
  • Exomes 𝑓: 0.47 (8 hom.)
• Consequence: LRTM2 NM_001039029.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRTM2	NM_001039029.3	c.-281G>A		5_prime_UTR_variant	1/5	ENST00000299194.6
CACNA2D4	NM_172364.5	c.2552-9069C>T		intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRTM2	ENST00000299194.6	c.-281G>A		5_prime_UTR_variant	1/5	2	NM_001039029.3	P1
CACNA2D4	ENST00000382722.10	c.2552-9069C>T		intron_variant		1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62790 AN: 152042 Hom.: 14391 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.465 AC: 40 AN: 86 Hom.: 8 Cov.: 0 AF XY: 0.453 AC XY: 29 AN XY: 64

Gnomad4 AFR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.583

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.413 AC: 62832 AN: 152160 Hom.: 14404 Cov.: 33 AF XY: 0.418 AC XY: 31066 AN XY: 74392

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.631

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.424

Alfa AF: 0.456 Hom.: 11728

Bravo AF: 0.393

Asia WGS AF: 0.522 AC: 1815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	10
Dann	Benign	0.82

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: rs4765845; hg19: chr12-1929958;