NM_019594.4:c.-8-11C>A

Variant names:

• chr9-128907146-C-A
• rs7860319
• NM_019594.4:c.-8-11C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019594.4(LRRC8A):​c.-8-11C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRC8A NM_019594.4 intron
• Scores: Splicing: ADA: 0.0001355
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.445
• Publications: 0 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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• agammaglobulinemia 5, autosomal dominant

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	NM_019594.4	MANE Select	c.-8-11C>A		intron	N/A	NP_062540.2	Q8IWT6
	LRRC8A	NM_001127244.2		c.-8-11C>A		intron	N/A	NP_001120716.1	Q8IWT6
	LRRC8A	NM_001127245.2		c.-8-11C>A		intron	N/A	NP_001120717.1	Q8IWT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	ENST00000372600.9	TSL:1 MANE Select	c.-8-11C>A		intron	N/A	ENSP00000361682.4	Q8IWT6
	LRRC8A	ENST00000372599.7	TSL:1	c.-8-11C>A		intron	N/A	ENSP00000361680.3	Q8IWT6
	LRRC8A	ENST00000964735.1		c.-19C>A		5_prime_UTR	Exon 1 of 2	ENSP00000634794.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438046 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 711354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 39192

South Asian (SAS) AF: 0.00 AC: 0 AN: 84674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095216

Other (OTH) AF: 0.0000168 AC: 1 AN: 59356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.5
DANN	Benign	0.73
PhyloP100		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.036
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: rs7860319; hg19: chr9-131669425;