1-89935503-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001134479.2(LRRC8D):​c.2435G>A​(p.Arg812His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

LRRC8D
NM_001134479.2 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
LRRC8D (HGNC:16992): (leucine rich repeat containing 8 VRAC subunit D) Enables volume-sensitive anion channel activity. Involved in cellular response to osmotic stress; organic acid transport; and protein hexamerization. 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06584695).
BS2
High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRC8DNM_001134479.2 linkuse as main transcriptc.2435G>A p.Arg812His missense_variant 3/3 ENST00000337338.9 NP_001127951.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRC8DENST00000337338.9 linkuse as main transcriptc.2435G>A p.Arg812His missense_variant 3/32 NM_001134479.2 ENSP00000338887 P1
LRRC8DENST00000394593.7 linkuse as main transcriptc.2435G>A p.Arg812His missense_variant 3/31 ENSP00000378093 P1

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00130
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
251072
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000664
AC:
97
AN:
1461862
Hom.:
0
Cov.:
33
AF XY:
0.0000646
AC XY:
47
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00158
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152358
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00130
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000921
Hom.:
0
Bravo
AF:
0.000461
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 05, 2021The c.2435G>A (p.R812H) alteration is located in exon 3 (coding exon 1) of the LRRC8D gene. This alteration results from a G to A substitution at nucleotide position 2435, causing the arginine (R) at amino acid position 812 to be replaced by a histidine (H). 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
0.090
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
23
DANN
Benign
0.97
DEOGEN2
Benign
0.024
T;T
Eigen
Uncertain
0.59
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
.;D
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.48
N;N
REVEL
Uncertain
0.30
Sift
Benign
0.54
T;T
Sift4G
Benign
0.56
T;T
Polyphen
0.87
P;P
Vest4
0.56
MVP
0.093
MPC
1.4
ClinPred
0.066
T
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.37
gMVP
0.42

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: rs142018032; hg19: chr1-90401062; API