19-7899106-C-T

Variant names:

• chr19-7899106-C-T
• rs377048254
• NM_025061.6:c.584C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_025061.6(LRRC8E):​c.584C>T​(p.Pro195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,612,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0820
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034742117).

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.584C>T	p.Pro195Leu	missense	Exon 3 of 3	NP_079337.2
	LRRC8E	NM_001268284.3		c.584C>T	p.Pro195Leu	missense	Exon 4 of 4	NP_001255213.1	Q6NSJ5
	LRRC8E	NM_001268285.3		c.197C>T	p.Pro66Leu	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.584C>T	p.Pro195Leu	missense	Exon 3 of 3	ENSP00000306524.5	Q6NSJ5
	LRRC8E	ENST00000618098.4	TSL:3	c.584C>T	p.Pro195Leu	missense	Exon 4 of 4	ENSP00000479953.1	Q6NSJ5
	LRRC8E	ENST00000907356.1		c.584C>T	p.Pro195Leu	missense	Exon 3 of 3	ENSP00000577415.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000960 AC: 24 AN: 249900 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1460624 Hom.: 1 Cov.: 38 AF XY: 0.000146 AC XY: 106 AN XY: 726438

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86234

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1111284

Other (OTH) AF: 0.000116 AC: 7 AN: 60354

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.5
DANN	Benign	0.71
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.082
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.014
Sift	Benign	0.30	T
Sift4G	Benign	0.22	T
Polyphen		0.073	B
Vest4		0.043
MVP		0.26
MPC		0.26
ClinPred		0.0093	T
GERP RS		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.30
Mutation Taster		=87/13	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: rs377048254; hg19: chr19-7963991; COSMIC: COSV60718086; COSMIC: COSV60718086;