19-7899741-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025061.6(LRRC8E):c.1219C>T(p.Leu407Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

Genes affected

LRRC8E (HGNC:26272): (leucine rich repeat containing 8 VRAC subunit E) This gene encodes a member of a small, conserved family of proteins with similar structure, including a string of extracellular leucine-rich repeats. A related protein was shown to be involved in B-cell development. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2012]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC8E	NM_025061.6	c.1219C>T	p.Leu407Phe	missense_variant	3/3	ENST00000306708.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8E	ENST00000306708.11	c.1219C>T	p.Leu407Phe	missense_variant	3/3	1	NM_025061.6	P1
	ENST00000539278.1	n.3802G>A		non_coding_transcript_exon_variant	1/1
LRRC8E	ENST00000618098.4	c.1219C>T	p.Leu407Phe	missense_variant	4/4	3		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.1219C>T (p.L407F) alteration is located in exon 3 (coding exon 2) of the LRRC8E gene. This alteration results from a C to T substitution at nucleotide position 1219, causing the leucine (L) at amino acid position 407 to be replaced by a phenylalanine (F). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.061	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.33		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.78
MPC		0.95
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.55

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: chr19-7964626;