rs941959

Variant names:

• chr9-128898608-T-C
• rs941959
• NM_019594.4:c.-8-8549T>C

Variant summary

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

The NM_019594.4(LRRC8A):​c.-8-8549T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 152,354 control chromosomes in the GnomAD database, including 145 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 0.037 (145 hom., cov: 32)
• Consequence: LRRC8A NM_019594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8A	NM_019594.4	c.-8-8549T>C		intron_variant	Intron 2 of 3	ENST00000372600.9	NP_062540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC8A	ENST00000372600.9	c.-8-8549T>C		intron_variant	Intron 2 of 3	1	NM_019594.4	ENSP00000361682.4
LRRC8A	ENST00000372599.7	c.-8-8549T>C		intron_variant	Intron 1 of 2	1		ENSP00000361680.3
LRRC8A	ENST00000259324.5	c.-8-8549T>C		intron_variant	Intron 2 of 3	2		ENSP00000259324.5

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5622 AN: 152236 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0320

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

GnomAD4 genome AF: 0.0369 AC: 5620 AN: 152354 Hom.: 145 Cov.: 32 AF XY: 0.0355 AC XY: 2648 AN XY: 74508

African (AFR) AF: 0.0113 AC: 471 AN: 41586

American (AMR) AF: 0.0321 AC: 491 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.0448 AC: 476 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0586 AC: 3988 AN: 68026

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0466 Hom.: 186

Bravo AF: 0.0347

Asia WGS AF: 0.00837 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.7
DANN	Benign	0.48
PhyloP100		0.44
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: rs941959; hg19: chr9-131660887;