1-89582841-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001369817.2(LRRC8B):ā€‹c.191A>Gā€‹(p.Asn64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000024 ( 0 hom. )

Consequence

LRRC8B
NM_001369817.2 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.42
Variant links:
Genes affected
LRRC8B (HGNC:30692): (leucine rich repeat containing 8 VRAC subunit B) Contributes to volume-sensitive anion channel activity. Involved in anion transmembrane transport. Located in cytoplasm and plasma membrane. Is integral component of plasma membrane. Part of ion channel complex. [provided by Alliance of Genome Resources, Apr 2022]
LRRC8C-DT (HGNC:53731): (LRRC8C divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0989849).
BS2
High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRC8BNM_001369817.2 linkuse as main transcriptc.191A>G p.Asn64Ser missense_variant 5/6 ENST00000330947.7
LRRC8BNM_001134476.2 linkuse as main transcriptc.191A>G p.Asn64Ser missense_variant 7/8
LRRC8BNM_001369819.2 linkuse as main transcriptc.191A>G p.Asn64Ser missense_variant 6/7
LRRC8BNM_015350.4 linkuse as main transcriptc.191A>G p.Asn64Ser missense_variant 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRC8BENST00000330947.7 linkuse as main transcriptc.191A>G p.Asn64Ser missense_variant 5/65 NM_001369817.2 P1
LRRC8C-DTENST00000655657.3 linkuse as main transcriptn.1284T>C non_coding_transcript_exon_variant 4/4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
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
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
251018
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135638
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000796
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000239
AC:
35
AN:
1461888
Hom.:
0
Cov.:
34
AF XY:
0.0000193
AC XY:
14
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000880
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 07, 2023The c.191A>G (p.N64S) alteration is located in exon 5 (coding exon 1) of the LRRC8B gene. This alteration results from a A to G substitution at nucleotide position 191, causing the asparagine (N) at amino acid position 64 to be replaced by a serine (S). 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
0.072
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.024
.;T;T;T;T;T
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;.;.;.;D;D
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.099
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
.;L;L;L;L;.
MutationTaster
Benign
0.98
D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.4
N;.;.;N;N;N
REVEL
Benign
0.11
Sift
Benign
0.065
T;.;.;T;T;T
Sift4G
Uncertain
0.049
D;.;.;T;T;T
Polyphen
0.79
.;P;P;P;P;.
Vest4
0.11, 0.080, 0.078
MutPred
0.40
Gain of glycosylation at N64 (P = 0.0339);Gain of glycosylation at N64 (P = 0.0339);Gain of glycosylation at N64 (P = 0.0339);Gain of glycosylation at N64 (P = 0.0339);Gain of glycosylation at N64 (P = 0.0339);Gain of glycosylation at N64 (P = 0.0339);
MVP
0.093
MPC
0.41
ClinPred
0.18
T
GERP RS
5.0
Varity_R
0.21
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769275630; hg19: chr1-90048400; API