chr9-128884150-G-T

Variant names:

• chr9-128884150-G-T
• rs10988141
• NM_019594.4:c.-115-1865G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019594.4(LRRC8A):​c.-115-1865G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0636 in 152,228 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.064 (455 hom., cov: 32)
• Consequence: LRRC8A NM_019594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019594.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	NM_019594.4	MANE Select	c.-115-1865G>T		intron	N/A	NP_062540.2
	LRRC8A	NM_001127244.2		c.-116+1241G>T		intron	N/A	NP_001120716.1
	LRRC8A	NM_001127245.2		c.-9+1900G>T		intron	N/A	NP_001120717.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	ENST00000372600.9	TSL:1 MANE Select	c.-115-1865G>T		intron	N/A	ENSP00000361682.4
	LRRC8A	ENST00000372599.7	TSL:1	c.-9+1900G>T		intron	N/A	ENSP00000361680.3
	LRRC8A	ENST00000259324.5	TSL:2	c.-116+1241G>T		intron	N/A	ENSP00000259324.5

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9678 AN: 152110 Hom.: 456 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.0758

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0636 AC: 9677 AN: 152228 Hom.: 455 Cov.: 32 AF XY: 0.0604 AC XY: 4492 AN XY: 74418

African (AFR) AF: 0.0170 AC: 707 AN: 41544

American (AMR) AF: 0.0798 AC: 1219 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 550 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4826

European-Finnish (FIN) AF: 0.0515 AC: 546 AN: 10592

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0923 AC: 6279 AN: 68012

Other (OTH) AF: 0.0750 AC: 158 AN: 2106

Alfa AF: 0.0792 Hom.: 1208

Bravo AF: 0.0658

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.98
DANN	Benign	0.74
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10988141; hg19: chr9-131646429;