rs941959

Positions:

• chr9-128898608-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
LRRC8A	NM_019594.4	c.-8-8549T>C		intron_variant		ENST00000372600.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8A	ENST00000372600.9	c.-8-8549T>C		intron_variant		1	NM_019594.4	P1
LRRC8A	ENST00000372599.7	c.-8-8549T>C		intron_variant		1		P1
LRRC8A	ENST00000259324.5	c.-8-8549T>C		intron_variant		2		P1

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

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0448

Gnomad4 NFE AF: 0.0586

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0495 Hom.: 61

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

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

LitVar

Other links and lift over

dbSNP: rs941959; hg19: chr9-131660887;