Genetic Variant LRRC8A:c.-8-11C>T (chr9-128907146-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_019594.4(LRRC8A):c.-8-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,590,410 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 160 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 145 hom. )

Consequence

LRRC8A
NM_019594.4 intron

Scores

Splicing: ADA: 0.000004060

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.445

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 9-128907146-C-T is Benign according to our data. Variant chr9-128907146-C-T is described in ClinVar as [Benign]. Clinvar id is 1257143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8A	NM_019594.4 link	c.-8-11C>T		intron_variant	Intron 2 of 3	ENST00000372600.9	NP_062540.2	Q8IWT6A0A024R892

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRC8A	ENST00000372600.9 link	c.-8-11C>T	intron_variant	Intron 2 of 3	1	NM_019594.4	ENSP00000361682.4	Q8IWT6
LRRC8A	ENST00000372599.7 link	c.-8-11C>T	intron_variant	Intron 1 of 2	1		ENSP00000361680.3	Q8IWT6
LRRC8A	ENST00000259324.5 link	c.-8-11C>T	intron_variant	Intron 2 of 3	2		ENSP00000259324.5	Q8IWT6

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3751

AN:

152250

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0853

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.00674

AC:

1643

AN:

243688

Hom.:

AF XY:

0.00490

AC XY:

645

AN XY:

131554

show subpopulations

Gnomad AFR exome

AF:

0.0863

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.00128

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.000171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000271

Gnomad OTH exome

AF:

0.00302

GnomAD4 exome

AF:

0.00259

AC:

3718

AN:

1438042

Hom.:

145

Cov.:

AF XY:

0.00222

AC XY:

1581

AN XY:

711352

show subpopulations

Gnomad4 AFR exome

AF:

0.0887

Gnomad4 AMR exome

AF:

0.00573

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.000366

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000100

Gnomad4 OTH exome

AF:

0.00541

GnomAD4 genome

AF:

0.0247

AC:

3770

AN:

152368

Hom.:

160

Cov.:

AF XY:

0.0237

AC XY:

1764

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.0855

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.00540

Hom.:

Bravo

AF:

0.0282

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

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

-0.42

CADD

Benign

7.9

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000041

dbscSNV1_RF

Benign

0.040

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