chr9-128908178-T-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.1014T>C(p.Tyr338Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,768 control chromosomes in the GnomAD database, including 33,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5162 hom., cov: 31)

Exomes 𝑓: 0.19 ( 28691 hom. )

Consequence

LRRC8A
NM_019594.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.78

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=-0.63).

BP6

Variant 9-128908178-T-C is Benign according to our data. Variant chr9-128908178-T-C is described in ClinVar as Benign. ClinVar VariationId is 403060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.78 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8A	NM_019594.4 link	c.1014T>C	p.Tyr338Tyr	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.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 3 of 4	1	NM_019594.4	ENSP00000361682.4	Q8IWT6
LRRC8A	ENST00000372599.7 link	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 2 of 3	1		ENSP00000361680.3	Q8IWT6
LRRC8A	ENST00000259324.5 link	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 3 of 4	2		ENSP00000259324.5	Q8IWT6

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36369

AN:

151884

Hom.:

5158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.251

GnomAD2 exomes

AF:

0.197

AC:

49560

AN:

251302

AF XY:

0.201

show subpopulations

Gnomad AFR exome

AF:

0.409

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.206

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.191

AC:

278756

AN:

1461766

Hom.:

28691

Cov.:

AF XY:

0.194

AC XY:

140740

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.413

AC:

13836

AN:

33480

American (AMR)

AF:

0.129

AC:

5750

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

5346

AN:

26136

East Asian (EAS)

AF:

0.212

AC:

8428

AN:

39700

South Asian (SAS)

AF:

0.288

AC:

24824

AN:

86258

European-Finnish (FIN)

AF:

0.124

AC:

6627

AN:

53306

Middle Eastern (MID)

AF:

0.279

AC:

1607

AN:

5768

European-Non Finnish (NFE)

AF:

0.180

AC:

199844

AN:

1111998

Other (OTH)

AF:

0.207

AC:

12494

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

16674

33348

50021

66695

83369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7192

14384

21576

28768

35960

<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:

0.239

AC:

36395

AN:

152002

Hom.:

5162

Cov.:

AF XY:

0.237

AC XY:

17606

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.399

AC:

16543

AN:

41418

American (AMR)

AF:

0.167

AC:

2554

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

670

AN:

3470

East Asian (EAS)

AF:

0.191

AC:

986

AN:

5162

South Asian (SAS)

AF:

0.290

AC:

1392

AN:

4800

European-Finnish (FIN)

AF:

0.126

AC:

1337

AN:

10590

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.179

AC:

12187

AN:

67980

Other (OTH)

AF:

0.248

AC:

522

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1311

2622

3932

5243

6554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.203

Hom.:

8600

Bravo

AF:

0.249

Asia WGS

AF:

0.201

AC:

697

AN:

3478

EpiCase

AF:

0.191

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.63

CADD

Benign

8.9

(source)

DANN

Benign

0.43

PhyloP100

2.8

Mutation Taster

=96/4

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