1-89583257-A-C

Position:

• chr1-89583257-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001369817.2(LRRC8B):​c.607A>C​(p.Lys203Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 0.0000041 (0 hom.)
• Consequence: LRRC8B NM_001369817.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

Genes affected

LRRC8B (HGNC:30692): (leucine rich repeat containing 8 VRAC subunit B) Contributes to volume-sensitive anion channel activity. Involved in anion transmembrane transport. Located in cytoplasm and plasma membrane. Is integral component of plasma membrane. Part of ion channel complex. [provided by Alliance of Genome Resources, Apr 2022]

LRRC8C-DT (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13556182).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC8B	NM_001369817.2	c.607A>C	p.Lys203Gln	missense_variant	5/6	ENST00000330947.7	NP_001356746.1
LRRC8B	NM_001134476.2	c.607A>C	p.Lys203Gln	missense_variant	7/8		NP_001127948.1
LRRC8B	NM_001369819.2	c.607A>C	p.Lys203Gln	missense_variant	6/7		NP_001356748.1
LRRC8B	NM_015350.4	c.607A>C	p.Lys203Gln	missense_variant	8/9		NP_056165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC8B	ENST00000330947.7	c.607A>C	p.Lys203Gln	missense_variant	5/6	5	NM_001369817.2	ENSP00000332674.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.00000540

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.607A>C (p.K203Q) alteration is located in exon 5 (coding exon 1) of the LRRC8B gene. This alteration results from a A to C substitution at nucleotide position 607, causing the lysine (K) at amino acid position 203 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.59
DEOGEN2	Benign	0.024	T;T;T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	.;.;.;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.26	.;.;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.58	.;.;T;T;T
Sift4G	Benign	0.60	.;.;T;T;T
Polyphen		0.42	B;B;B;B;.
Vest4		0.16, 0.19, 0.15
MutPred		0.12		Loss of ubiquitination at K203 (P = 6e-04);Loss of ubiquitination at K203 (P = 6e-04);Loss of ubiquitination at K203 (P = 6e-04);Loss of ubiquitination at K203 (P = 6e-04);Loss of ubiquitination at K203 (P = 6e-04);
MVP		0.11
MPC		0.62
ClinPred		0.47	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.33

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: rs1363581361; hg19: chr1-90048816;