chr12-1820792-G-A

Variant names:

• chr12-1820792-G-A
• rs4765845
• NM_001039029.3:c.-281G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

CACNA2D4 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LRTM2	NM_001039029.3	c.-281G>A		5_prime_UTR_variant	Exon 1 of 5	ENST00000299194.6	NP_001034118.1
CACNA2D4	NM_172364.5	c.2552-9069C>T		intron_variant	Intron 26 of 37	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTM2	ENST00000299194.6	c.-281G>A		5_prime_UTR_variant	Exon 1 of 5	2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000382722.10	c.2552-9069C>T		intron_variant	Intron 26 of 37	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2552-9069C>T		intron_variant	Intron 26 of 36	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2477-9069C>T		intron_variant	Intron 25 of 36	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2360-9069C>T		intron_variant	Intron 26 of 36	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2360-9069C>T		intron_variant	Intron 26 of 37	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*798-10205C>T		intron_variant	Intron 26 of 36	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.392-9069C>T		intron_variant	Intron 4 of 14	1		ENSP00000440231.2

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.583 AC: 14 AN: 24

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.432 AC: 19 AN: 44

Other (OTH) AF: 0.500 AC: 6 AN: 12

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

African (AFR) AF: 0.214 AC: 8891 AN: 41506

American (AMR) AF: 0.410 AC: 6279 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1711 AN: 3464

East Asian (EAS) AF: 0.631 AC: 3255 AN: 5160

South Asian (SAS) AF: 0.435 AC: 2102 AN: 4828

European-Finnish (FIN) AF: 0.580 AC: 6141 AN: 10588

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 33004 AN: 67986

Other (OTH) AF: 0.424 AC: 897 AN: 2114

Alfa AF: 0.459 Hom.: 18684

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
PhyloP100		1.4
PromoterAI		-0.0084	Neutral
Mutation Taster		=300/0	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: rs4765845; hg19: chr12-1929958;