10-84222237-C-A

Variant names:

• chr10-84222237-C-A
• NM_001017924.5:c.1336G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001017924.5(LRIT2):​c.1336G>T​(p.Val446Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRIT2 NM_001017924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

LRIT2 (HGNC:23443): (leucine rich repeat, Ig-like and transmembrane domains 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31382698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRIT2	NM_001017924.5	c.1336G>T	p.Val446Leu	missense_variant	Exon 3 of 3	ENST00000372113.7	NP_001017924.1
LRIT2	NM_001284223.1	c.1366G>T	p.Val456Leu	missense_variant	Exon 4 of 4		NP_001271152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRIT2	ENST00000372113.7	c.1336G>T	p.Val446Leu	missense_variant	Exon 3 of 3	1	NM_001017924.5	ENSP00000361185.3
LRIT2	ENST00000538192.5	c.1366G>T	p.Val456Leu	missense_variant	Exon 4 of 4	1		ENSP00000438264.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1336G>T (p.V446L) alteration is located in exon 3 (coding exon 3) of the LRIT2 gene. This alteration results from a G to T substitution at nucleotide position 1336, causing the valine (V) at amino acid position 446 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.093
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.89	.;P
Vest4		0.12
MutPred		0.59		.;Loss of sheet (P = 0.0817);
MVP		0.52
MPC		0.018
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.19
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-85981993;