Variant 1-89583939-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001369817.2(LRRC8B):c.1289A>G(p.Asn430Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,216 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

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

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

LRRC8B
NM_001369817.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0540

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]

LRRC8B links:

LRRC8C-DT (HGNC:53731): (LRRC8C divergent transcript)

LRRC8C-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055749416).

BP6

Variant 1-89583939-A-G is Benign according to our data. Variant chr1-89583939-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2356357.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRRC8B	NM_001369817.2 linkuse as main transcript	c.1289A>G	p.Asn430Ser	missense_variant	5/6	ENST00000330947.7
LRRC8B	NM_001134476.2 linkuse as main transcript	c.1289A>G	p.Asn430Ser	missense_variant	7/8
LRRC8B	NM_001369819.2 linkuse as main transcript	c.1289A>G	p.Asn430Ser	missense_variant	6/7
LRRC8B	NM_015350.4 linkuse as main transcript	c.1289A>G	p.Asn430Ser	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8B	ENST00000330947.7 linkuse as main transcript	c.1289A>G	p.Asn430Ser	missense_variant	5/6	5	NM_001369817.2	P1
LRRC8C-DT	ENST00000655657.3 linkuse as main transcript	n.701-515T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000215

AC:

AN:

250630

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000933

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.013

DANN

Benign

0.55

DEOGEN2

Benign

0.028

T;T;T;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.72

.;.;.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.2

N;N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

1.1

.;.;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

.;.;T;T

Sift4G

Benign

1.0

.;.;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.040, 0.033

MVP

0.043

MPC

0.41

ClinPred

0.021

GERP RS

-5.7

Varity_R

0.015

gMVP

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over