chr9-128907208-C-T

Position:

• chr9-128907208-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The ENST00000372600.9(LRRC8A):​c.44C>T​(p.Pro15Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC8A ENST00000372600.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRRC8A. . Gene score misZ 3.3754 (greater than the threshold 3.09). Trascript score misZ 5.0212 (greater than threshold 3.09). GenCC has associacion of gene with agammaglobulinemia 5, autosomal dominant, autosomal agammaglobulinemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC8A	NM_019594.4	c.44C>T	p.Pro15Leu	missense_variant	3/4	ENST00000372600.9	NP_062540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC8A	ENST00000372600.9	c.44C>T	p.Pro15Leu	missense_variant	3/4	1	NM_019594.4	ENSP00000361682.4
LRRC8A	ENST00000372599.7	c.44C>T	p.Pro15Leu	missense_variant	2/3	1		ENSP00000361680.3
LRRC8A	ENST00000259324.5	c.44C>T	p.Pro15Leu	missense_variant	3/4	2		ENSP00000259324.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460738 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 15 of the LRRC8A protein (p.Pro15Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LRRC8A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.84
MutPred		0.51		Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);
MVP		0.46
MPC		2.1
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.40
gMVP		0.84

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: rs1309555967; hg19: chr9-131669487;