1-89584056-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369817.2(LRRC8B):​c.1406G>A​(p.Arg469His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,614,088 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0047 ( 18 hom., cov: 32)
Exomes 𝑓: 0.0034 ( 166 hom. )

Consequence

LRRC8B
NM_001369817.2 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.33
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0029286444).
BP6
Variant 1-89584056-G-A is Benign according to our data. Variant chr1-89584056-G-A is described in ClinVar as [Benign]. Clinvar id is 770489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRC8BNM_001369817.2 linkuse as main transcriptc.1406G>A p.Arg469His missense_variant 5/6 ENST00000330947.7
LRRC8BNM_001134476.2 linkuse as main transcriptc.1406G>A p.Arg469His missense_variant 7/8
LRRC8BNM_001369819.2 linkuse as main transcriptc.1406G>A p.Arg469His missense_variant 6/7
LRRC8BNM_015350.4 linkuse as main transcriptc.1406G>A p.Arg469His missense_variant 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRC8BENST00000330947.7 linkuse as main transcriptc.1406G>A p.Arg469His missense_variant 5/65 NM_001369817.2 P1
LRRC8C-DTENST00000655657.3 linkuse as main transcriptn.701-632C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00467
AC:
711
AN:
152158
Hom.:
18
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0259
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.0506
Gnomad SAS
AF:
0.00331
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00574
GnomAD3 exomes
AF:
0.00938
AC:
2354
AN:
250828
Hom.:
54
AF XY:
0.00784
AC XY:
1063
AN XY:
135564
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.0363
Gnomad ASJ exome
AF:
0.000398
Gnomad EAS exome
AF:
0.0537
Gnomad SAS exome
AF:
0.00196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000883
Gnomad OTH exome
AF:
0.00523
GnomAD4 exome
AF:
0.00345
AC:
5042
AN:
1461812
Hom.:
166
Cov.:
34
AF XY:
0.00322
AC XY:
2342
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0346
Gnomad4 ASJ exome
AF:
0.000344
Gnomad4 EAS exome
AF:
0.0764
Gnomad4 SAS exome
AF:
0.00245
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000351
Gnomad4 OTH exome
AF:
0.00300
GnomAD4 genome
AF:
0.00467
AC:
711
AN:
152276
Hom.:
18
Cov.:
32
AF XY:
0.00537
AC XY:
400
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.0259
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.0509
Gnomad4 SAS
AF:
0.00332
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00306
Hom.:
13
Bravo
AF:
0.00719
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00825
AC:
1001
Asia WGS
AF:
0.0180
AC:
63
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.75
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
4.7
DANN
Benign
0.71
DEOGEN2
Benign
0.037
T;T;T;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.68
.;.;.;T
MetaRNN
Benign
0.0029
T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-1.1
N;N;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
2.7
.;.;N;N
REVEL
Benign
0.019
Sift
Benign
1.0
.;.;T;T
Sift4G
Benign
0.65
.;.;T;T
Polyphen
0.0
B;B;B;B
Vest4
0.074, 0.060
MVP
0.043
MPC
0.64
ClinPred
0.00058
T
GERP RS
-0.63
Varity_R
0.0087
gMVP
0.12

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: rs3795832; hg19: chr1-90049615; API