Variant chr1-89583515-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001369817.2(LRRC8B):c.865T>G(p.Cys289Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRRC8B
NM_001369817.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.93

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRRC8B	NM_001369817.2 linkuse as main transcript	c.865T>G	p.Cys289Gly	missense_variant	5/6	ENST00000330947.7
LRRC8B	NM_001134476.2 linkuse as main transcript	c.865T>G	p.Cys289Gly	missense_variant	7/8
LRRC8B	NM_001369819.2 linkuse as main transcript	c.865T>G	p.Cys289Gly	missense_variant	6/7
LRRC8B	NM_015350.4 linkuse as main transcript	c.865T>G	p.Cys289Gly	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8B	ENST00000330947.7 linkuse as main transcript	c.865T>G	p.Cys289Gly	missense_variant	5/6	5	NM_001369817.2	P1
LRRC8C-DT	ENST00000655657.3 linkuse as main transcript	n.701-91A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726930

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.865T>G (p.C289G) alteration is located in exon 5 (coding exon 1) of the LRRC8B gene. This alteration results from a T to G substitution at nucleotide position 865, causing the cysteine (C) at amino acid position 289 to be replaced by a glycine (G). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

.;.;.;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.1

.;.;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

.;.;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.90, 0.87

MutPred

0.66

Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);

MVP

0.75

MPC

1.6

ClinPred

1.0

GERP RS

5.3

Varity_R

0.92

gMVP

0.55

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over