2-80302808-C-T

Position:

• chr2-80302808-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295057.4(LRRTM1):​c.1012G>A​(p.Gly338Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00276 in 1,613,858 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (57 hom.)
• Consequence: LRRTM1 ENST00000295057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024371445).
• BP6: Variant 2-80302808-C-T is Benign according to our data. Variant chr2-80302808-C-T is described in ClinVar as [Benign]. Clinvar id is 778820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1964/152318) while in subpopulation AFR AF= 0.0426 (1770/41574). AF 95% confidence interval is 0.0409. There are 36 homozygotes in gnomad4. There are 942 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1964 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRTM1	NM_178839.5	c.1012G>A	p.Gly338Ser	missense_variant	2/2	ENST00000295057.4	NP_849161.2
CTNNA2	NM_001282597.3	c.1057-90403C>T		intron_variant		ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRTM1	ENST00000295057.4	c.1012G>A	p.Gly338Ser	missense_variant	2/2	1	NM_178839.5	ENSP00000295057	P1
CTNNA2	ENST00000402739.9	c.1057-90403C>T		intron_variant		1	NM_001282597.3	ENSP00000384638

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1961 AN: 152200 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00353 AC: 882 AN: 249832 Hom.: 12 AF XY: 0.00268 AC XY: 363 AN XY: 135344

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00170 AC: 2490 AN: 1461540 Hom.: 57 Cov.: 30 AF XY: 0.00148 AC XY: 1076 AN XY: 727072

Gnomad4 AFR exome AF: 0.0471

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.000403

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.0129 AC: 1964 AN: 152318 Hom.: 36 Cov.: 33 AF XY: 0.0126 AC XY: 942 AN XY: 74478

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00228 Hom.: 15

Bravo AF: 0.0147

ESP6500AA AF: 0.0393 AC: 173

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00415 AC: 504

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.69	.;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.97	N;N
REVEL	Benign	0.054
Sift	Benign	0.87	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.054
MVP		0.068
ClinPred		0.0058	T
GERP RS		4.4
Varity_R		0.039
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61734034; hg19: chr2-80529933;