NM_019594.4:c.1476T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_019594.4(LRRC8A):c.1476T>C(p.Arg492Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,612,392 control chromosomes in the GnomAD database, including 399,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 31457 hom., cov: 33)

Exomes 𝑓: 0.71 ( 368182 hom. )

Consequence

LRRC8A
NM_019594.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.39

Publications

24 publications found

Variant links:

Genes affected

LRRC8A (HGNC:19027): (leucine rich repeat containing 8 VRAC subunit A) This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC8A Gene-Disease associations (from GenCC):

autosomal agammaglobulinemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
agammaglobulinemia 5, autosomal dominant
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

LRRC8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 9-128908640-T-C is Benign according to our data. Variant chr9-128908640-T-C is described in ClinVar as Benign. ClinVar VariationId is 403061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8A	NM_019594.4 link	c.1476T>C	p.Arg492Arg	synonymous_variant	Exon 3 of 4	ENST00000372600.9	NP_062540.2	Q8IWT6A0A024R892

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRC8A	ENST00000372600.9 link	c.1476T>C	p.Arg492Arg	synonymous_variant	Exon 3 of 4	1	NM_019594.4	ENSP00000361682.4	Q8IWT6
LRRC8A	ENST00000372599.7 link	c.1476T>C	p.Arg492Arg	synonymous_variant	Exon 2 of 3	1		ENSP00000361680.3	Q8IWT6
LRRC8A	ENST00000259324.5 link	c.1476T>C	p.Arg492Arg	synonymous_variant	Exon 3 of 4	2		ENSP00000259324.5	Q8IWT6

Frequencies

GnomAD3 genomes

AF:

0.613

AC:

93242

AN:

152018

Hom.:

31449

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.819

Gnomad AMR

AF:

0.745

Gnomad ASJ

AF:

0.735

Gnomad EAS

AF:

0.671

Gnomad SAS

AF:

0.664

Gnomad FIN

AF:

0.803

Gnomad MID

AF:

0.678

Gnomad NFE

AF:

0.722

Gnomad OTH

AF:

0.648

GnomAD2 exomes

AF:

0.704

AC:

173997

AN:

247290

AF XY:

0.707

show subpopulations

Gnomad AFR exome

AF:

0.295

Gnomad AMR exome

AF:

0.795

Gnomad ASJ exome

AF:

0.735

Gnomad EAS exome

AF:

0.681

Gnomad FIN exome

AF:

0.803

Gnomad NFE exome

AF:

0.722

Gnomad OTH exome

AF:

0.716

GnomAD4 exome

AF:

0.707

AC:

1031785

AN:

1460256

Hom.:

368182

Cov.:

AF XY:

0.707

AC XY:

513637

AN XY:

726400

show subpopulations

African (AFR)

AF:

0.289

AC:

9678

AN:

33478

American (AMR)

AF:

0.787

AC:

35140

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.746

AC:

19494

AN:

26132

East Asian (EAS)

AF:

0.712

AC:

28242

AN:

39678

South Asian (SAS)

AF:

0.675

AC:

58181

AN:

86228

European-Finnish (FIN)

AF:

0.803

AC:

41859

AN:

52120

Middle Eastern (MID)

AF:

0.729

AC:

4203

AN:

5766

European-Non Finnish (NFE)

AF:

0.714

AC:

793337

AN:

1111832

Other (OTH)

AF:

0.690

AC:

41651

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

20789

41578

62366

83155

103944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19756

39512

59268

79024

98780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.613

AC:

93288

AN:

152136

Hom.:

31457

Cov.:

AF XY:

0.621

AC XY:

46164

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.307

AC:

12751

AN:

41476

American (AMR)

AF:

0.745

AC:

11394

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.735

AC:

2553

AN:

3472

East Asian (EAS)

AF:

0.671

AC:

3468

AN:

5166

South Asian (SAS)

AF:

0.663

AC:

3202

AN:

4826

European-Finnish (FIN)

AF:

0.803

AC:

8509

AN:

10592

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.722

AC:

49100

AN:

67988

Other (OTH)

AF:

0.647

AC:

1367

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1610

3220

4829

6439

8049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.680

Hom.:

125261

Bravo

AF:

0.595

Asia WGS

AF:

0.654

AC:

2274

AN:

3478

EpiCase

AF:

0.715

EpiControl

AF:

0.723

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Agammaglobulinemia 5, autosomal dominant

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.14

(source)

DANN

Benign

0.54

PhyloP100

-2.4

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over