19-7899180-G-C

Variant names:

• chr19-7899180-G-C
• rs777004836
• NM_025061.6:c.658G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025061.6(LRRC8E):​c.658G>C​(p.Val220Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V220I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13617572).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025061.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8E	NM_025061.6	MANE Select	c.658G>C	p.Val220Leu	missense	Exon 3 of 3	NP_079337.2
	LRRC8E	NM_001268284.3		c.658G>C	p.Val220Leu	missense	Exon 4 of 4	NP_001255213.1	Q6NSJ5
	LRRC8E	NM_001268285.3		c.271G>C	p.Val91Leu	missense	Exon 2 of 2	NP_001255214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8E	ENST00000306708.11	TSL:1 MANE Select	c.658G>C	p.Val220Leu	missense	Exon 3 of 3	ENSP00000306524.5	Q6NSJ5
	LRRC8E	ENST00000618098.4	TSL:3	c.658G>C	p.Val220Leu	missense	Exon 4 of 4	ENSP00000479953.1	Q6NSJ5
	LRRC8E	ENST00000907356.1		c.658G>C	p.Val220Leu	missense	Exon 3 of 3	ENSP00000577415.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		6.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.072
Sift	Benign	0.66	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.16		Loss of sheet (P = 0.0084)
MVP		0.64
MPC		0.82
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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: rs777004836; hg19: chr19-7964065;