Variant 1-89933372-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001134479.2(LRRC8D):c.304A>G(p.Thr102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 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: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRRC8D
NM_001134479.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.18

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]

LRRC8D links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046848923).

BP6

Variant 1-89933372-A-G is Benign according to our data. Variant chr1-89933372-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3120994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC8D	NM_001134479.2 linkuse as main transcript	c.304A>G	p.Thr102Ala	missense_variant	3/3	ENST00000337338.9	NP_001127951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC8D	ENST00000337338.9 linkuse as main transcript	c.304A>G	p.Thr102Ala	missense_variant	3/3	2	NM_001134479.2	ENSP00000338887	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

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

Oct 10, 2023

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

0.060

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.015

T;T;.;T;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.50

.;T;T;T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.047

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;.;.;.;.

MutationTaster

Benign

0.63

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.13

N;N;N;N;N;N

REVEL

Benign

0.025

Sift

Benign

0.79

T;T;T;T;T;T

Sift4G

Benign

0.70

T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;.;.

Vest4

0.014

MVP

0.12

MPC

0.57

ClinPred

0.017

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.060

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.

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