19-7898751-A-C

Variant names:

• chr19-7898751-A-C
• NM_025061.6:c.229A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025061.6(LRRC8E):​c.229A>C​(p.Ile77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.607

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]

ENSG00000214248 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06398535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8E	NM_025061.6	c.229A>C	p.Ile77Leu	missense_variant	Exon 3 of 3	ENST00000306708.11	NP_079337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC8E	ENST00000306708.11	c.229A>C	p.Ile77Leu	missense_variant	Exon 3 of 3	1	NM_025061.6	ENSP00000306524.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229A>C (p.I77L) alteration is located in exon 3 (coding exon 2) of the LRRC8E gene. This alteration results from a A to C substitution at nucleotide position 229, causing the isoleucine (I) at amino acid position 77 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	0.061
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.52
DEOGEN2	Benign	0.00038	T;T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	.;T;T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N;N;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N;.;.;.;.
REVEL	Benign	0.0080
Sift	Benign	0.60	T;.;.;.;.
Sift4G	Benign	0.90	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.14
MutPred		0.24		Gain of disorder (P = 0.0818);Gain of disorder (P = 0.0818);Gain of disorder (P = 0.0818);Gain of disorder (P = 0.0818);Gain of disorder (P = 0.0818);
MVP		0.31
MPC		0.25
ClinPred		0.049	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.20

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: chr19-7963636;