NM_025061.6:c.529C>A

Variant names:

• chr19-7899051-C-A
• rs1311246907
• NM_025061.6:c.529C>A

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.529C>A​(p.Pro177Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.146
• 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=0.07273269).

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.529C>A	p.Pro177Thr	missense	Exon 3 of 3	NP_079337.2
	LRRC8E	NM_001268284.3		c.529C>A	p.Pro177Thr	missense	Exon 4 of 4	NP_001255213.1	Q6NSJ5
	LRRC8E	NM_001268285.3		c.142C>A	p.Pro48Thr	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.529C>A	p.Pro177Thr	missense	Exon 3 of 3	ENSP00000306524.5	Q6NSJ5
	LRRC8E	ENST00000618098.4	TSL:3	c.529C>A	p.Pro177Thr	missense	Exon 4 of 4	ENSP00000479953.1	Q6NSJ5
	LRRC8E	ENST00000907356.1		c.529C>A	p.Pro177Thr	missense	Exon 3 of 3	ENSP00000577415.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460962 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111636

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

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	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.5
DANN	Benign	0.83
DEOGEN2	Benign	0.00038	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.15
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.016
Sift	Benign	0.27	T
Sift4G	Benign	0.57	T
Polyphen		0.0040	B
Vest4		0.049
MVP		0.57
MPC		0.29
ClinPred		0.22	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.27
Mutation Taster		=92/8	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: rs1311246907; hg19: chr19-7963936;