19-7899145-C-G

Variant names:

• chr19-7899145-C-G
• rs767909728
• NM_025061.6:c.623C>G

Variant summary

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

The NM_025061.6(LRRC8E):​c.623C>G​(p.Ala208Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LRRC8E NM_025061.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184

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=0.034554034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8E	NM_025061.6	c.623C>G	p.Ala208Gly	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.623C>G	p.Ala208Gly	missense_variant	Exon 3 of 3	1	NM_025061.6	ENSP00000306524.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250902 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135684

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 SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461334 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.5
DANN	Benign	0.78
DEOGEN2	Benign	0.00072	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.54	N;.
REVEL	Benign	0.028
Sift	Benign	0.31	T;.
Sift4G	Benign	0.42	T;T
Polyphen		0.011	B;B
Vest4		0.074
MutPred		0.089		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.32
MPC		0.27
ClinPred		0.036	T
GERP RS		-2.5
Varity_R		0.030
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs767909728; hg19: chr19-7964030;